bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–03–29
forty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.
  2. Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1.
  3. Enhancing Proteasome Activity in T Cells Alleviates Exhaustion and Improves Antitumor Immunity.
  4. ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation.
  5. Disruption of metabolic licensing by JAK inhibitors constrains CD8 T cell activation and effector function.
  6. Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity.
  7. Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion.
  8. KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3.
  9. PAK4 functions as an immune suppressor by reprogramming the phosphatidylcholine metabolism of CD8 + T cells within the glioblastoma tumor microenvironment.
  10. Systemic Cysteine Elevation Sustains T-Cell Activation to Potentiate PD-1 Blockade.
  11. One cell, many fates: transcriptional networks governing CD8+ T cell differentiation.
  12. Role of Succinate Dehydrogenase in Age-Related Th17 Inflammation.
  13. Targeting Mettl8-Tcf1 axis promotes CD8+ TPEX differentiation and antitumor immunity.
  14. The research progress on the role of glucose-6-phosphate dehydrogenase in immune regulation.
  15. Targeting BATF: A new strategy for cancer immunotherapy.
  16. FLT3-ITD scaffolds PKCι-STAT1 to drive noncanonical S727 phosphorylation and CD276-driven CD8+ T-cell exhaustion in AML.
  17. Exercise and CD8+ T cells: mechanisms of immune modulation in antitumor responses.
  18. A Triple-Hit Multi-Omics Framework for Psoriasis: Microbial Metabolic Remodeling and Immune Cell Methylome Signature Associated with an AMP-Dominant Lesional Program.
  19. Differential Radiosensitivity in T-Cell Subsets: Metabolic and Antioxidative Mechanisms Underlying Naïve T-Cell Vulnerability.
  20. Bie-Jia-Jian Pill: Inhibiting tumor glycolysis and promoting CD8+ cell-mediated anti-tumor immunity by targeting HIF-1α-PI3K/AKT/mTOR and CCL20 in hepatocellular carcinoma.
  21. Reduced tumor control in males can result from impaired CD4+ T-cell help through the CD40L-CD40 pathway.
  22. Correction for Li et al., Functionally heterogeneous intratumoral CD4+CD8+ double-positive T cells can give rise to single-positive T cells.
  23. Maternal Krüppel-like factor 2 (KLF2)+ CD4 T cells promote fertility and fetal tolerance.
  24. Central memory T cells: stem-like biology, pathogenic roles in autoimmunity, and therapeutic applications.
  25. CD8 + T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration.
  26. American Ginseng (Panax quinquefolius) Extracts (G1899) Ameliorate Immunosenescence via Regulation of T Cell Populations and Aging-Related Proteins in a Mouse Model Induced by D-Galactose and Tert-Butyl Hydroperoxide.
  27. NHE1-Mediated Metabolic Reprogramming in Cancer.
  28. Single-cell assessment of iron content in primary human T cells using laser ablation inductively coupled plasma mass spectrometry.
  29. Subversion of kynurenine-induced AHR activation in CD8 T cells by kynureninase-expressing antigen-presenting cells.
  30. TOPK Suppresses the CD8+ T Cell Antitumor Immunity via Modulation of IRF5 Expression.
  31. Cell-Intrinsic Type I Interferon Signaling as a Pleiotropic Orchestrator of CD4 T Cell Immunity.
  32. Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.
  33. Unleashing T cell surveillance for the eradication of quiescent persister tumor cells resistant to neoadjuvant chemotherapy.
  34. Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.
  35. Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
  36. Copper Dyshomeostasis, Redox Buffering and Immune Aging Converge on Cuproptosis in Age-Related Diseases.
  37. T cell lymphomas: cancers of aberrant immune synapse signalling.
  38. The pivotal role of metabolism in shaping tumor-associated macrophages phenotype and function.
  39. Therapeutic scheduling of WEE1 inhibition preserves T cell function and promotes immune control of HPV⁺ tumors.
  40. The TCR in CAR T cell therapy: use it or lose it?
  41. Targeted inhibition of ITK activity with anti-CD3 antibody-modified calcium silicate nanoparticles loaded with novel 7H-Pyrrolo[2,3-d]pyrimidine derivatives for treating aplastic anemia.
  42. SIRT1 deficiency promotes age-related heart failure through enhancing ferroptosis via GATA4-HADHA-GPX4 axis.
  1. Cell Signal. 2026 Mar 23. pii: S0898-6568(26)00148-8. [Epub ahead of print]143 112496
    Lipid metabolic reprogramming of CD8+ T cells in the tumor microenvironment.
    Lujing Mao, Juan Zou, Huimin Jin, Wenyan Liao, Yukun Li, Daichao Wu.
      Metabolic reprogramming within the tumor microenvironment is a critical driver of CD8+ T cell dysfunction that limits the efficacy of cancer immunotherapy. While glucose and amino acid deprivation are well-characterized, lipid metabolic rewiring has emerged as a fundamental determinant of T cell fate. This review systematically examines the mechanisms by which the tumor microenvironment disrupts CD8+ T cell lipid metabolism to promote functional exhaustion and ferroptosis. We first discuss how local stressors such as hypoxia and acidosis alongside systemic host factors including obesity and hyperlipidemia synergistically impose a metabolic siege on infiltrating T cells. We then detail the molecular pathways of dysregulation revealed by recent lipidomic profiling, including CD36-mediated uptake of oxidized lipids that drives ferroptosis, as well as the dysregulation of cholesterol homeostasis that impairs TCR signaling and induces endoplasmic reticulum stress via the IRE1α-XBP1 axis, which directly drives the transcriptional expression of immune checkpoints. Finally, we evaluate therapeutic strategies such as pharmacological modulation of lipid transporters and metabolic engineering of CAR-T cells which hold promise for restoring metabolic fitness and reinvigorating antitumor immunity.
    Keywords:  CD8(+) T cells; Ferroptosis; Immunotherapy; Lipid metabolism; T cell exhaustion; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.cellsig.2026.112496
  2. Cell Metab. 2026 Mar 23. pii: S1550-4131(26)00085-9. [Epub ahead of print]
    Tissue and CD4 T cell subset dependence on the amino acid transporter SLC38A1.
    Ayaka Sugiura, Katherine L Beier, Channing Chi, Darren R Heintzman, Xiang Ye, Melissa M Wolf, Andrew R Patterson, Jacqueline-Yvonne Cephus, Hanna S Hong, Jeffrey M Perera, Costas A Lyssiotis, Dawn C Newcomb, Jeffrey C Rathmell.
      Amino acid (AA) uptake is essential for T cell metabolism and function, but how tissue sites and inflammation affect CD4+ T cell subset requirements for specific AAs remains uncertain. Here, we tested CD4+ T cell AA demands with in vitro and in vivo CRISPR screens and identified subset- and tissue-specific dependencies on the AA transporter SLC38A1 (SNAT1). While dispensable for T cell persistence and expansion in vivo in lung inflammation, SLC38A1 was critical for Th1, but not Th17, cell-driven experimental autoimmune encephalomyelitis (EAE) and contributed to Th1 cell-driven inflammatory bowel disease. SLC38A1 deficiency reduced mTORC1 signaling and glycolytic activity in Th1 cells, in part by reducing glutamine uptake and disrupting hexosamine biosynthesis and redox regulation. Pharmacological inhibition of SLC38 transporters also delayed Th1-mediated EAE but did not affect lung inflammation. CD4+ T cells thus have subset- and tissue-specific nutrient transporter dependencies that may guide new metabolic approaches for selective immunotherapies.
    Keywords:  Slc38a1; T cell; amino acid transport; glutaminolysis
    DOI:  https://doi.org/10.1016/j.cmet.2026.02.016
  3. Cancer Res. 2026 Mar 26.
    Enhancing Proteasome Activity in T Cells Alleviates Exhaustion and Improves Antitumor Immunity.
    Ander de Blas, Massimo Andreatta, Asier Antoñana-Vildosola, Paloma Velasco-Beltrán, Leire Egia-Mendikute, Borja Jimenez-Lasheras, Alexandre Bosch, Adrián Barreira-Manrique, Iker Oyenarte, So Young Lee, Christoph Heuser-Loy, Jeremy G Baldwin, Roland C Schelker, Azucena Martín-Santos, Fabio Mastrogiovanni, Mikel Azkargorta, Felix Elortza, James D Sutherland, Veronica Torrano, Ana M Aransay, Lorena Pérez-Gutiérrez, Alena Gros, Santiago J Carmona, Luca Gattinoni, June Ereño-Orbea, Endika Prieto-Fernández, Asis Palazon.
      Chronic T cell receptor (TCR) stimulation combined with adverse conditions in the tumor microenvironment (TME), such as hypoxia and nutrient deprivation, frequently results in T cell exhaustion. Exhausted T cells (TEX) experience oxidative stress, which causes an accumulation of oxidized proteins within the cells. We hypothesized that oxidized protein formation might exceed proteasomal degradation capacity, leading to their accumulation and impairing T cell fitness. Single-cell transcriptomics analysis across 16 tumor types revealed increased expression of proteasome genes in TEX compared to non-exhausted T cells. In a robust in vitro model for the generation of human TEX, the cells exhibited hallmarks of exhaustion, with higher levels of reactive oxygen species (ROS)-induced protein oxidation and increased expression of proteasome genes. Pharmacological and genetic enhancement of proteasome activity delayed the onset of T cell exhaustion, improved T cell fitness, and translated into superior antitumor immunity and tumor control. These findings identify proteasome modulation as a promising strategy to counteract TME-driven T cell dysfunction, potentially overcoming a major obstacle to the efficacy of cell-based immunotherapies in solid tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-1246
  4. Nat Immunol. 2026 Mar 27.
    ZFP148 is a transcriptional repressor of cytolytic effector CD8+ T cell differentiation.
    Tong Xiao, Xingyu Chen, No-Joon Song, Ryan J Brown, Anjun Ma, Jay K Mandula, Amir Yousif, Yi Wang, Minh Quynh May Le, Jianying Li, Fengxia Gao, Bella Weaver, Heng-Yi Chen, Fang-Yun Lay, Debasish Sundi, Maria Velegraki, Payton Weltge, Juanita L Merchant, Mark P Rubinstein, Kenneth J Oestreich, Chan-Wang Jerry Lio, Hazem E Ghoneim, Xue Li, Dan Theodorescu, Gang Xin, Qin Ma, Weiguo Cui, Zihai Li.
      Progenitor CD8+ T cells differentiate into effector and exhausted progenies during chronic antigen stimulation; however, mechanisms that restrain exhaustion and sustain effector differentiation remain incompletely defined. Here we identified the transcription factor ZFP148 as a repressor of CD8+ T cell effector differentiation. ZFP148-deficient CD8+ T cells displayed increased frequency of cytolytic effector cells and reduced frequency of exhausted cells compared with Zfp148fl/fl controls during chronic viral infection. Mechanistically, ZFP148 limited the chromatin accessibility of effector-driving transcription factor motifs and directly repressed expression of the transcription factor KLF2. Furthermore, conditional ZFP148 ablation in CD8+ T cells synergized with programmed cell death-1 blockade to improve tumor control in syngeneic mouse models. Consistently, cancer patients with lower ZNF148 expression in tumor-infiltrating CD8+ T cells showed improved responsiveness to immunotherapies. Collectively, our study identifies ZFP148 as a transcriptional repressor of CD8+ T cell effector differentiation and highlights its therapeutic potential for enhancing antitumor immunity.
    DOI:  https://doi.org/10.1038/s41590-026-02461-2
  5. Cell Death Dis. 2026 Mar 24.
    Disruption of metabolic licensing by JAK inhibitors constrains CD8 T cell activation and effector function.
    Luisina Inés Onofrio, Carolina Abrate, Ingrid Strusberg, Liliana Morales, Danilo Guillermo Ceschin, Carolina Lucía Montes, Cinthia Carolina Stempin, Eva Acosta Rodríguez.
      Janus kinase inhibitors (JAKis) are widely prescribed for autoimmune diseases, but their use is associated with increased infection risk. The mechanisms underlying this susceptibility remain unclear. CD8 T cells play a central role in antimicrobial defence, yet little is known about how JAKis reprogramme their activation and effector programmes. Here, we investigated naive and memory CD8 T cells from healthy donors stimulated in vitro in the presence of clinically relevant JAK inhibitors targeting JAK1 (JAK1i), JAK1/2 (JAK1/2i), or JAK1/3 (JAK1/3i). Flow cytometry, SCENITH, transmission electron microscopy, and RNA-seq were used to evaluate metabolic and functional programmes. We found that JAKis uncoupled phenotypic activation from metabolic reprogramming. Functionally, JAKi-treated CD8 T cells exhibited reduced activation and produced lower amounts of cytokines and cytotoxic molecules. Notably, even JAKi-treated memory CD8 T cells that upregulated CD69 and CD25 failed to engage glycolysis, showing decreased GLUT1 expression and glucose uptake. SCENITH profiling confirmed diminished glucose dependence and a shift toward mitochondrial reliance, despite reduced mitochondrial potential and structural alterations. Transcriptomic and protein analyses further revealed decreased mTOR activity and increased p53-associated transcripts, consistent with impaired growth and stress signalling. CD8 T cells from rheumatoid arthritis patients under JAKi therapy were analysed ex vivo for translational validation. These cells showed similar metabolic and signalling alterations, underscoring their clinical relevance. Altogether, these findings identify JAKis as disruptors of metabolic and signalling pathways in CD8 T cells, providing a mechanistic link between impaired effector function and the increased infection risk observed in treated patients.
    DOI:  https://doi.org/10.1038/s41419-026-08610-7
  6. Sci Immunol. 2026 Mar 27. 11(117): eaeb1459
    Palmitate-induced mitochondrial damage restricts histone acetylation in CD8 T cells to impair antitumor immunity.
    Silvia Tiberti, Sara Gennari, Martina Romeo, Ilir Sheraj, Mohamed Faisal Kassir, Juan Fernández-García, Carina B Nava Lauson, Roberta Noberini, Carlotta Catozzi, Tiziano Dallavilla, Mattia Ballerini, Alessia Loffreda, Simona G Codreanu, Stacy D Sherrod, Katrina L Leaptrot, Alexandra C Schrimpe-Rutledge, John A McLean, Martin H Schaefer, Simona Rodighiero, Tiziana Bonaldi, Sarah-Maria Fendt, Besim Ogretmen, Sara Sdelci, Luigi Nezi, Teresa Manzo.
      Lipid accumulation in the tumor microenvironment is a hallmark of solid tumors, with increased palmitate (PA) availability fostering tumor progression. Although PA's direct effects on cancer cells are well described, its impact on CD8 T cells [cytotoxic T lymphocytes (CTLs)] remains unclear. Here, we show that PA irreversibly impairs CTL mitochondrial metabolism, leading to the loss of effector functions and compromised antitumor immunity. PA-induced mitochondrial dysfunction reduced histone acetylation and chromatin accessibility, suppressing transcription of genes involved in T cell replication and effector programs. We identified sphingosine kinase 2 (SPHK2) as a key mediator of PA-induced dysfunction, with pharmacological inhibition of SPHK2 restoring mitochondrial fitness, rescuing CTL effector function, and promoting antitumor activity. These findings uncover a distinct mechanism by which PA drives immune evasion in tumors and highlight SPHK2 as a potential therapeutic target to enhance T cell-based immunotherapies.
    DOI:  https://doi.org/10.1126/sciimmunol.aeb1459
  7. Nature. 2026 Mar 25.
    Exposed phosphatidylserine is an inhibitory molecule in T cell exhaustion.
    Christopher B Medina, Ewelina Sobierajska, Minghao Gong, Daniel T McManus, Maheshwor Thapa, Judong Lee, Se Jin Im, Jason E Toombs, Joshua M Mitchell, Yating Wang, Jennifer W Carlisle, Gordon J Freeman, Viraj A Master, Suresh S Ramalingam, Haydn T Kissick, Shuzhao Li, Rolf A Brekken, Rafi Ahmed.
      In cancer and chronic infection, CD8 T cell exhaustion is hallmarked by expression of inhibitory receptors such as PD1, TIM3, LAG3 and others1-3. Thus, inhibitory molecule focus has been limited to cell-surface proteins. Here we evaluate the surface lipid metabolite phosphatidylserine (PS) as a regulator of exhaustion. PS primarily localizes to the inner plasma membrane of live cells but is well known to be externalized to the outer membrane during cell death. The role of exposed PS on live immune cells is less clear. We show that viable, antigen-specific CD8 T cells externalize PS during lymphocytic choriomeningitis virus (LCMV) infection. T cell activation induced initial PS exposure, and chronic antigen stimulation sustained externalization. Transcriptomic and lipidomic analyses also identified PS accumulation in exhausted CD8 T cells. To evaluate a role for exposed PS in exhaustion, we treated LCMV chronically infected mice with a PS-targeting antibody (mch1N11)4 and found that it expanded LCMV-specific CD8 responses. PD1+TCF1+ stem-like CD8 T cells downregulated quiescence-associated gene modules and increased proliferation after antibody treatment, highlighting an inhibitory role for PS. Mechanistically, exposed PS on T cells functioned extrinsically to suppress dendritic cell immunostimulatory phenotypes, in turn limiting CD8 T cell responses. PS-targeting antibody with anti-PDL1 synergized to increase CD8 responses and improve viral control. Finally, we show that PD1+ CD8 T cells from human tumours can also expose PS. In summary, we detail CD8 T cell PS biology and provide insight into a mechanism by which exposed PS functions as a 'non-classical' extrinsic inhibitory molecule in exhaustion.
    DOI:  https://doi.org/10.1038/s41586-026-10266-4
  8. Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2533700123
    KLF2 overrides the resident memory CD8 T cell differentiation program, in opposition to KLF3.
    Taylor A DePauw, Kexin Gai, Jian Shen, Nicholas J Maurice, Ka Hyun Rhee, William J Valente, Christine H O'Connor, Weiguo Cui, Changwei Peng, Stephen C Jameson.
      Numerous transcriptional regulators have been associated with the differentiation pathways that lead to recirculating vs. tissue-resident memory T cells. However, it is unclear whether independent, coordinated expression of these regulators is required to determine residency vs. recirculation or whether there is a hierarchy, with some factors playing a dominant role in controlling T cell trafficking. We report that ablation of the gene encoding Kruppel-like factor 2 (KLF2) during CD8+ T cell activation leads to rapid transcriptional reprogramming, such that effector T cells fail to recirculate and prematurely acquire canonical phenotypic and transcriptional characteristics of resident memory cells (TRM). Klf2-deficient memory CD8+ T cells retained the capacity to undergo recall responses, including in vivo pathogen control. These data suggest that KLF2 diverts CD8+ T cells from the TRM differentiation program. In contrast, ablation of another member of the KLF family, KLF3, enhanced differentiation of some recirculating T cell subsets and limited production of TRM in lymphoid tissues. However, both KLF2 and KLF3 were required for differentiation of long-lived effector cells, suggesting cooperation between these factors in some situations. These findings indicate that KLFs occupy a central nexus in coordinating activated CD8+ T cell differentiation and trafficking.
    Keywords:  KLF2; memory CD8 T cells; tissue-resident
    DOI:  https://doi.org/10.1073/pnas.2533700123
  9. Oncogene. 2026 Mar 23.
    PAK4 functions as an immune suppressor by reprogramming the phosphatidylcholine metabolism of CD8 + T cells within the glioblastoma tumor microenvironment.
    Lin Yao, Heyang Gao, Zuopeng Su, Guozheng Zhao, Liyan Tang, Shuo Feng, Yuting Ma, Xiao Zhang, Ming Feng, Jialiang Qian, Yanyan Li, Ting Sun, Jiangang Liu, Hao Wang, Youxin Zhou.
      Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that represents a significant therapeutic challenge because of its immunosuppressive tumor microenvironment (TME). GBM employs multiple sophisticated mechanisms for immune evasion, including proinflammatory cytokine secretion and immune cell effector function impairment. Due to these complex immune evasion strategies, immunotherapies are effective in only a minority of GBM patients. Herein, we identified P21-activated kinase 4 (PAK4) as a critical immunosuppressive gene that is highly expressed in GBM and actively promotes tumor progression. Mechanistically, PAK4 mediates transforming growth factor-beta 1 (TGF-β1) release from GBM cells, triggering PI3K/AKT/NF-κB signalling pathway activation in CD8 + T cells, which consequently upregulates phospholipase A2 group IVA (PLA2G4A) expression. PLA2G4A activation triggers phosphatidylcholine (PC) depletion in CD8 + T cells, damages mitochondrial and lysosomal functions, inducing subsequent mitophagic flux suppression, which culminates in the functional exhaustion of CD8 + T cells. Furthermore, PLA2G4A inhibitor treatment effectively reduces CD8 + T cell exhaustion while enhancing T cell cytotoxic capacity. Finally, combined PAK4 inhibitor and anti-PD-L1 therapy increases the CD8 + T cell cytotoxic function and suppresses tumor growth. Overall, our study results suggest that targeting PAK4 could be a potential strategy for GBM immunotherapy.
    DOI:  https://doi.org/10.1038/s41388-026-03734-8
  10. bioRxiv. 2026 Mar 18. pii: 2026.03.16.711688. [Epub ahead of print]
    Systemic Cysteine Elevation Sustains T-Cell Activation to Potentiate PD-1 Blockade.
    Xiaoshuang Wang, Zi Wang, Yuqi Guo, Fangxi Xu, Jinhui Zhu, Scott C Thomas, Deepak Saxena, Jinghang Xie, Xin Li.
      Resistance to immune checkpoint inhibition remains a major barrier in pancreatic cancer treatment. Here, we show that concurrent administration of probiotics restores sensitivity to anti-PD-1 therapy in pancreatic cancer mouse models. Mice treated with the combination of anti-PD-1 and probiotics demonstrate robust tumor control, accompanied by enrichment of microbial pathways governing cysteine biosynthesis, elevated serum cysteine levels, and increased T cell function. Serum cysteine levels, rather than intratumoral cysteine concentrations, inversely correlate with tumor burden. Functionally, cysteine directly promotes T cell survival, activation, and cytotoxicity while its restriction induces uncoupled transcriptional-translational stress and impairs T cell function. Oral cysteine supplementation synergizes with anti-PD-1 therapy in pancreatic cancer mice, reducing tumor burden and enhancing intratumoral T cell activation, phenocopying probiotics-mediated immune restoration. These findings suggest systemic cysteine availability as a tractable metabolic target to enhance cancer immunotherapy.
    DOI:  https://doi.org/10.64898/2026.03.16.711688
  11. Immunol Cell Biol. 2026 Mar 24.
    One cell, many fates: transcriptional networks governing CD8+ T cell differentiation.
    M Zeeshan Chaudhry, Gabrielle T Belz.
      A recent study in Nature shows that CD8+ T cell differentiation trajectories are governed by transcription factors, with distinct single-state and multi-state regulators directing cell fate decisions.
    DOI:  https://doi.org/10.1111/imcb.70106
  12. Aging Cell. 2026 Apr;25(4): e70451
    Role of Succinate Dehydrogenase in Age-Related Th17 Inflammation.
    Evelyn Ocegueda, Gabrielle Chase, Michaella Niceforo, Aida Javidan, Lydia Gugliuzza, Jingting Yu, Rachel Y Kang, Ava Lankowski, Olivia Stefanik, Kailey Leclerc, Yolander Valentine, Micah J Drummond, Jude T Deeney, Josephine S Modica-Napolitano, Elizabeth A Proctor, Hatice Hasturk, Barbara S Nikolajczyk, Leena P Bharath.
      Age-related cellular changes negatively impact CD4+ T cell function. Our prior work showed that mitochondrial complex II (succinate dehydrogenase [SDH]) expression was upregulated in T cells from older (O) adults (60-80 years old). T cells from older adults also produced higher amounts of cytokines generally considered proinflammatory, such as Th17 cytokines IL-17A/F and IL-21, and the Th-17-supportive cytokine IL-6, compared to T cells from younger (Y) adults (25-40 years old). The objective of our study is to evaluate whether hyperactivation of SDH is required for the induction of proinflammatory cytokines and the mechanistic link between SDH and Th17 cytokine production. CD4+ T cells were isolated from lean normoglycemic younger (avg: 31.58 years; BMI 21.14 kg/m2) and older (avg: 64.81 years; BMI 21.95 kg/m2) adults. SDH was pharmacologically and genetically modulated, and mitochondrial structure, function, metabolites, and cytokine production were quantified. SDH activation in T cells from older adults induced heightened oxidation of succinate, disrupted the fumarate-to-succinate ratio, stabilized HIF-1α, and promoted Th17 cytokines. Genetic and pharmacological inhibition of SDH in T cells from older adults lowered proinflammatory cytokine production, whereas exogenous addition of cell-permeable succinate induced SDH protein in T cells from younger adults and recapitulated the proinflammatory Th17 profile observed in T cells from older adults. These data establish a mechanistic link between SDH and Th17 inflammation.
    Keywords:  Aging; Complex II; Cytokines; Mitochondria; SDH; T cells; Th17 cytokines
    DOI:  https://doi.org/10.1111/acel.70451
  13. J Exp Med. 2026 May 04. pii: e20250424. [Epub ahead of print]223(5):
    Targeting Mettl8-Tcf1 axis promotes CD8+ TPEX differentiation and antitumor immunity.
    Jiaxi Song, Dan Cui, Jiabao Wang, Xuewei Qi, Jiaxin Ma, Qing Liu, Jing Yang, Haoyu Yu, Lilin Ye, Qizhao Huang, Jia Li, Fengyin Li.
      CD8+ T cell exhaustion represents a major obstacle to effective cancer immunotherapy. While stem-like progenitor exhausted T (TPEX) cells can differentiate into intermediate (Int-TEX) and terminally exhausted (TEX) subsets, the epigenetic regulation of this process is unclear. We identify the RNA methyltransferase Mettl8 as a critical regulator, with expression significantly higher in TPEX than in TEX subsets. In anti-PD-1 responding non-small cell lung cancer patients, Mettl8 and the stemness factor TCF7 were downregulated. In murine models, Mettl8 deletion restrained tumor progression by driving TPEX differentiation into effective Int-TEX cells. Mechanistically, Mettl8 stabilizes Tcf7 mRNA via m3C modification and enhances Tcf1 protein expression. Additionally, Mettl8 interacts with Tcf1 to facilitate chromatin looping at the Tox locus, maintaining TPEX stemness. Pharmacological Mettl8 inhibition promoted TPEX-to-Int-TEX differentiation and tumor control. Combining this inhibition with anti-PD-1 therapy yielded synergistic efficacy. Our findings establish Mettl8 as a pivotal regulator of TPEX fate and a promising therapeutic target for enhancing immunotherapy.
    DOI:  https://doi.org/10.1084/jem.20250424
  14. PeerJ. 2026 ;14 e20971
    The research progress on the role of glucose-6-phosphate dehydrogenase in immune regulation.
    Dingmei Zhang, Yizhong Wang.
      Glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the pentose phosphate pathway (PPP), plays a pivotal role in immune regulation by regulating metabolic reprogramming and redox homeostasis of immune cells. It mediates the production of nicotinamide adenine dinucleotide phosphate (NADPH) and ribose-5-phosphate (R5P), which are essential for the activation, proliferation, and effector function of T lymphocytes, B lymphocytes, macrophages, and neutrophils-specifically promoting T/B cell-mediated adaptive immunity and macrophage/neutrophil-mediated innate immune responses. Abnormal G6PD activity (deficiency or overexpression) is closely associated with the pathogenesis of immune-related diseases: G6PD deficiency increases susceptibility to autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus) and infectious diseases (e.g., hepatitis, malaria, COVID-19) by inducing oxidative stress and immune cell dysfunction; in tumor immunity, G6PD dualistically promotes tumor cell proliferation while regulating anti-tumor immunity via modulating cytoxic D8+ T cell exhaustion and macrophage polarization. Additionally, G6PD-targeted immunotherapies, including small-molecule inhibitors and gene therapy, have shown promising preclinical potential for treating immune-related diseases. These findings highlight G6PD as a key metabolic-immune hub, providing critical theoretical basis for understanding immune regulation mechanisms and developing novel diagnostic and therapeutic strategies for autoimmune diseases, infectious diseases, and tumors.
    Keywords:  Glucose-6-phosphate dehydrogenase; Immune cells; Immune regulation; Immune-related diseases; Therapeutic target
    DOI:  https://doi.org/10.7717/peerj.20971
  15. Biochim Biophys Acta Rev Cancer. 2026 Mar 20. pii: S0304-419X(26)00051-X. [Epub ahead of print] 189579
    Targeting BATF: A new strategy for cancer immunotherapy.
    Linyang Li, Xuwen Lin, Qun Wang, Sanhong Liu.
      Immunotherapy encompasses a variety of strategies for combating tumors, including the use of antibody drugs, cell transfer therapy, and tumor vaccines, but these approaches still face several challenges. Owing to advancements in single-cell sequencing technology, researchers have recently identified new therapeutic targets that enable T cells to penetrate tumor tissue more deeply and enhance their ability to attack tumor cells, thereby improving treatment outcomes. In this process, particularly under conditions of T cell exhaustion, the basic leucine zipper transcription factor ATF-like protein (BATF) plays a crucial role in the maturation and activity of T cells. BATF regulates the differentiation and function of T cells, thereby influencing their ability to combat tumor cells. Additionally, there is a positive feedback mechanism between BATF and PD-1 expression, which may also lead to T cells rapidly losing their ability to attack tumor cells. This review describes the latest advances in research on new targets for antitumour immunotherapy. It focuses on the role of BATF in the development and exhaustion of CD8+ T cells while summarizing the application of BATF as a new target in antitumor immunotherapy and the progress of related research. Our article highlights the importance of the BATF transcription factor in T cell development and exhaustion, outlines some of the challenges and contradictions encountered in BATF research as a new target in antitumor immunotherapy, and explains the potential causes of these contradictions. The aim of this review was to provide new insights and methods for antitumor immunotherapy.
    Keywords:  BATF; Drug resistance; Immunotherapy; T cell; Targeted therapy
    DOI:  https://doi.org/10.1016/j.bbcan.2026.189579
  16. Blood. 2026 Mar 24. pii: blood.2025032254. [Epub ahead of print]
    FLT3-ITD scaffolds PKCι-STAT1 to drive noncanonical S727 phosphorylation and CD276-driven CD8+ T-cell exhaustion in AML.
    Yun Wang, Shuzhao Chen, Shutong Liu, Zhijian Liang, Hailin Zheng, Chunhua Li, Qianqian Huang, Qi Liang, Ziang Zhu, Weida Wang, Yang Liang, Xiao-Jun Huang.
      FLT3-ITD mutation is associated with poor prognosis in acute myeloid leukemia (AML), yet its kinase-independent mechanisms remain unclear. To investigate kinase-independent immunosuppressive mechanisms in FLT3-ITD AML, we integrated single-cell RNA sequencing from two public datasets and multiparameter flow cytometry data from 104 primary patient samples, identifying profound CD8+ T cell exhaustion as a hallmark of the FLT3-ITD immune microenvironment. Mechanistically, FLT3-ITD acts as a mutation-specific scaffold that assembles a ternary complex with PKCι and STAT1, as demonstrated by co-immunoprecipitation and intracellular colocalization. This complex enables PKCι-mediated phosphorylation of STAT1 specifically at serine 727 (S727), driving CD276 transcription independent of the canonical tyrosine 701 (Y701) site. Chromatin immunoprecipitation, electrophoretic mobility shift, promoter-reporter assays, and phosphosite-mutant constructs confirmed that S727 phosphorylation is necessary and sufficient for CD276 transactivation. Multiplex immunohistochemistry of patient bone marrow validated co-elevation of pS727-STAT1 and CD276 in FLT3-ITD blasts, accompanied by CD8+ T cell depletion. Functionally, CD276 upregulation induced profound CD8+ T cell exhaustion, characterized by reduced cytotoxicity, impaired proliferation, diminished IFN-γ production and elevated inhibitory checkpoints expression. Targeting CD276 restored CD8+ T cell function by 1.2-1.7-fold (cytotoxicity), 1.4-1.7-fold (proliferation), 1.5-1.8-fold (IFN-γ secretion) and 25.4%-67.6% (checkpoints expression) in ex vivo co-culture. In patient-derived xenograft models, co-treatment with FLT3i (quizartinib) and CD276-targeting agents led to 72.9%-80.4% tumor burden reduction and enhanced CD8+ T cell function, outperforming quizartinib monotherapy. These findings define a scaffolded PKCι-pS727-STAT1 signaling axis that promotes immune evasion in FLT3-ITD AML, supporting combined FLT3 and CD276 targeting as a promising translational strategy in this aggressive leukemia subtype.
    DOI:  https://doi.org/10.1182/blood.2025032254
  17. J Mol Med (Berl). 2026 Mar 21. pii: 54. [Epub ahead of print]104(1):
    Exercise and CD8+ T cells: mechanisms of immune modulation in antitumor responses.
    Li Liu, Zhihao Deng, Ruiying Fang, Mi Zou, Junlin Ren, Yuan Gao, Jie Peng, Liang Hao.
      CD8+ T cells are the core effector cells of antitumor immunity. However, their functionality is vulnerable to metabolic stress within the tumor microenvironment (TME), and they experience significant inhibition from immunosuppressive signals, such as PD-1/PD-L1 and myeloid-derived suppressor cells (MDSC). This review explores how exercise enhances CD8+ T-cell antitumor efficacy through multidimensional synergistic mechanisms. At the molecular level, exercise stimulates the IL-15/IL-15Rα signaling pathway and triggers the release of myokines such as IL-6 and IL-7. These changes considerably boost CD8+ T-cell proliferation, viability, and granzyme B-dependent tumoricidal activity. Concurrently, exercise improves metabolic adaptation and sustains antitumor effects via metabolic reprogramming, which involves enhancing mitochondrial oxidative phosphorylation and increasing lactate-mediated stemness. Moreover, exercise optimizes TME vascular structure, downregulates PD-L1 expression, reduces MDSC proportion, and transforms the immunosuppressive environment, thus facilitating CD8+ T-cell infiltration and long-term function. Preclinical studies have verified that exercise works in tandem with immune checkpoint inhibitors, like anti-PD-1, to improve T-cell homing and counteract the depletion phenotype through the CXCR3-CXCL9/10 axis. Despite the positive progress, the mechanisms of exercise intensity, individual heterogeneity, and dynamic regulation of TME need to be explored in depth. Future studies need to combine multi-omics and dynamic immune monitoring to develop personalized exercise interventions based on CD8+ T-cell profiles. Exercise provides a low-cost, low-risk adjuvant strategy for cancer immunotherapy by targeting CD8+ T-cell function and TME remodeling, and its clinical translational potential needs large-scale validation.
    Keywords:  CD8+ T cells; Exercise; Immunomodulation; Tumor; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s00109-026-02659-9
  18. Life (Basel). 2026 Mar 20. pii: 516. [Epub ahead of print]16(3):
    A Triple-Hit Multi-Omics Framework for Psoriasis: Microbial Metabolic Remodeling and Immune Cell Methylome Signature Associated with an AMP-Dominant Lesional Program.
    Yoon Kyeong Lee, Hak Yong Kim, Donghwan Shim.
      The gut-skin axis is increasingly implicated in psoriasis pathogenesis, yet the cross-compartment convergence of molecular programs remains incompletely defined. We constructed a conceptual "Triple-Hit" multi-omics framework by integrating five independent public datasets spanning gut microbial functional remodeling (shotgun metagenomics), systemic immune cell methylomes (PBMC and CD8+ T-cell EPIC 850K), and lesional skin regulatory layers (miRNA and bulk RNA-seq). In the gut compartment, functional profiles exhibited a selective reduction in microbial lipid catabolic potential, including decreased fatty acid degradation and a lowered composite lipid degradation score, alongside heterogeneous shifts across SCFA-associated metabolic pathways. Systemically, PBMC methylomes revealed widespread regional remodeling (45,396 DMRs) enriched for membrane-proximal signaling and cytoskeletal programs, while CD8+ T cells showed specific epigenetic alterations in lipid- and glycosphingolipid-associated loci, suggesting a systemic metabolic-epigenetic alignment. In the skin, we identified a compact miRNA signature (168 DE-miRNAs) and a mechanistically interpretable, directionality-constrained miRNA-mRNA bridge that aligns with an AMP-dominant inflammatory transcriptome, consistent with reduced post-transcriptional restraint. Collectively, these findings support a convergent multi-omics framework linking putative microbial metabolic remodeling, systemic immune priming, and cutaneous effector programs. This study provides a systems-level perspective on psoriasis pathogenesis, highlighting the metabolic-epigenetic-transcriptional convergence as a potential avenue for therapeutic intervention.
    Keywords:  DNA methylation; antimicrobial peptides; gut–skin axis; immune cell epigenetics; lipid metabolism; microbial metabolism; multi-omics; psoriasis
    DOI:  https://doi.org/10.3390/life16030516
  19. Radiat Res. 2026 Mar 25. pii: eRADE-25-00083. [Epub ahead of print]
    Differential Radiosensitivity in T-Cell Subsets: Metabolic and Antioxidative Mechanisms Underlying Naïve T-Cell Vulnerability.
    Lorreta Yun-Tien Lin, Anika Kot, Albert J Fornace, Heng-Hong Li.
      T cells, which are generally highly sensitive to DNA damage-induced cell death, exhibit distinct responses to ionizing radiation (IR) depending on their differentiation state. In this study, we investigated the heightened radiosensitivity of naïve T cells (Tn) compared to memory T cells (Tm) through in vivo and in vitro models. Following whole-body irradiation (WBI), naïve T cells, particularly naïve CD8+ T cells, displayed significant depletion and delayed recovery, compared to their Tm counterparts. Transcriptomic analyses revealed similar p53 pathway activation in both Tn and Tm postirradiation but highlighted key differences in cytokine signaling and metabolic profiles between these two cell states. Tm cells showed elevated expression of survival-promoting cytokine receptors, anti-apoptotic genes, and mitochondrial respiratory activity, coupled with robust antioxidative defense systems, including increased glutathione synthesis and thioredoxin reductase activity. Supplementation with N-acetylcysteine, a reactive oxygen species (ROS) scavenger, partially mitigated Tn depletion after WBI, underscoring the role of oxidative stress in Tn radiosensitivity. These findings suggest that the metabolic and antioxidative adaptations of Tm confer greater intrinsic resilience against radiation-induced damage than those of Tn. This disparity underscores the importance of targeted interventions to preserve naïve T cell populations and maintain immune balance after radiation exposure.
    DOI:  https://doi.org/10.1667/RADE-25-00083
  20. J Ethnopharmacol. 2026 Mar 20. pii: S0378-8741(26)00405-8. [Epub ahead of print]365 121554
    Bie-Jia-Jian Pill: Inhibiting tumor glycolysis and promoting CD8+ cell-mediated anti-tumor immunity by targeting HIF-1α-PI3K/AKT/mTOR and CCL20 in hepatocellular carcinoma.
    Yang Liu, Xuemei Yang, Mengchen Qin, Weicong Chen, Changshun Liu, Wentao Jiang, Yiqin Wang, Sirui Tan, Haiyan Sun, Jingfei Chen, Haitao Sun, Songqi He.
       ETHNOPHARMACOLOGICAL RELEVANCE: The efficacy of immunotherapy for hepatocellular carcinoma (HCC) is often limited by an immunosuppressive tumor microenvironment (TME), largely driven by tumor metabolic reprogramming (the Warburg effect) that impairs CD8+ T cells. Targeting this metabolism to restore immunity is a promising strategy. Bie-Jia-Jian Pill (BJJP), a traditional formula for "softening hardness and dissipating masses," conceptually aligns with modulating the TME. However, its role in reprogramming tumor metabolism to enhance immunotherapy remains unclear.
    AIM OF THE STUDY: We aimed to investigate if BJJP enhances anti-tumor immunity by inhibiting the Warburg effect, elucidate its molecular mechanism, and evaluate its synergy with PD-L1 blockade.
    MATERIALS AND METHODS: Using UHPLC-MS, the major components of BJJP were analyzed and its efficacy was evaluated in combination with the PD-L1 neutralizing antibody for HCC treatment. CD8+ T cells and tumor markers were assessed in vitro and in vivo using flow cytometry. Transcriptomics, metabolomics, Seahorse metabolic assays, Western blotting, ELISA, and immunofluorescence staining were employed to identify and validate the mechanisms and targets of BJJP. Its targeting capabilities were confirmed by lentivirus and siRNA transfections, network pharmacology and molecular docking.
    RESULTS: BJJP suppressed HCC cell proliferation, growth and migration, promoted their apoptosis, reduced PD-L1 expression, and enhanced CD8+ T cell cytotoxicity and infiltration in the tumor. BJJP and immunotherapy exerted synergistic effects, including inhibiting tumor cell proliferation, increasing immune cell infiltration, and improving treatment efficacy. BJJP suppressed glycolysis in HCC cells, alleviated the excessive uptake of energy substrates, and reduced lactate accumulation in the microenvironment, thereby mitigating CD8+ T cell exhaustion. This glycolytic metabolic reprogramming was related to BJJP's effect on inhibiting the HIF-1α-PI3K/AKT/mTOR axis. Additionally, BJJP inhibited the downstream NF-κB activation, down-regulated CCL20, and alleviated the inhibitory effect of CCL20 against CD8+ T cells.
    CONCLUSION: BJJP targets the HIF-1α-PI3K/AKT/mTOR axis to reprogram tumor glycolysis, reduce CCL20 secretion, enhance CD8+ T cell immune response, and modulate the tumor microenvironment, thereby exerting anti-tumor effects against HCC. When used in combination with immunotherapy, BJJP can improve treatment efficacy, providing valuable evidence for clinical treatment.
    Keywords:  BJJP; CCL20; CD8(+) T cells; Glycolysis; HCC; HIF-1α-PI3K/AKT/mTOR
    DOI:  https://doi.org/10.1016/j.jep.2026.121554
  21. Cancer Immunol Res. 2026 Mar 25.
    Reduced tumor control in males can result from impaired CD4+ T-cell help through the CD40L-CD40 pathway.
    Katey S Hunt, Samantha Cooke, Lindsey M Kuehm, Tyson A Lobb, Emily Ebert, Smrithi Beeram, Ryan M Teague, Michelle Brennan, Melissa M Berrien-Elliott, Stephen T Ferris, Elise Alspach.
      Sex-based differences in cancer incidence are incompletely understood, but potential roles for the immune system are beginning to emerge. CD4+ T cells play a central role in coordinating antitumor immunity. In addition to cytokine production, CD40L expression on CD4+ T cells provides necessary helper signaling to dendritic cells that is required for the priming of cytotoxic tumor-specific CD8+ T cells. Despite these critical functions, the impact of biological sex on the CD4+ T-cell response to cancer remains unknown. Here, we demonstrate that impaired immune-mediated tumor control in male mice compared to female mice is driven by disparate CD4+ T-cell responses in a mouse model of bladder cancer. We found that CD40L expression was reduced on CD4+ T cells isolated from males via a mechanism predominantly driven by cell-intrinsic androgen receptor signaling, resulting in decreased dendritic cell licensing through CD40 within tumor-draining lymph nodes. These deficits resulted in decreased helper CD4+ T-cell frequencies and impaired CD8+ T-cell function within the male tumor microenvironment which could be rescued by targeting the CD40L-CD40 axis. Our findings identify a novel mechanism of CD4+ T cell-based sex differences in the immune response to cancer that impairs tumor control.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1115
  22. Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2606104123
    Correction for Li et al., Functionally heterogeneous intratumoral CD4+CD8+ double-positive T cells can give rise to single-positive T cells.
      
    DOI:  https://doi.org/10.1073/pnas.2606104123
  23. Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2519393123
    Maternal Krüppel-like factor 2 (KLF2)+ CD4 T cells promote fertility and fetal tolerance.
    Ngan N M Nguyen, Alexander E Brady, Abigail Russi, Giang Pham, Bo Li, Lucien H Turner, Michael Kotliar, Artem Barski, Xiaofei Sun, Sing Sing Way.
      Pregnancy requires expanded maternal tolerance to semiallogeneic fetal-expressed antigens to protect against fetal loss and other pregnancy complications. Our understanding of how this biological imperative works remains uncertain. Here we show pregnancy primes expansion of antigen-experienced Krüppel-like factor 2 (KLF2)+ CD4 T cells with fetal specificity, and that these maternal cells play an essential role in optimal fertility and protecting against fetal resorption. Antigen-experienced KLF2+ CD4 cells purified from pregnant dams are poised for IL10 production and suppress responder T cell proliferation in coculture. Mice with conditional loss of KLF2 in T cells become pregnant less efficiently after allogeneic mating with genetically discordant males, but not after syngeneic mating with genetically identical males. Impaired fertility is associated with diminished and variable early pregnancy progesterone levels, whereas progression from mating to pregnancy is restored with exogenous progesterone. To bypass fertility defects, complementary experiments show that initiating induced KLF2 deletion in CD4 T cells midgestation causes fetal resorption associated with expansion of activated fetal-specific CD8 effector T cells across maternal tissues, particularly in the uterine draining lymph node and at the maternal-fetal interface. Reciprocally, these phenotypes are overturned with CD8 T cell depletion or in mice reconstituted with CD4 cells from wild-type donors which upregulate KLF2 expression in pregnant recipients. These findings demonstrate that maternal KLF2+ CD4 T cells promote fetal tolerance and fertility, particularly during allogeneic pregnancy.
    Keywords:  CD4 T cells; pregnancy; prenatal infection; reproduction; tolerance
    DOI:  https://doi.org/10.1073/pnas.2519393123
  24. Clin Exp Rheumatol. 2026 Mar 12.
    Central memory T cells: stem-like biology, pathogenic roles in autoimmunity, and therapeutic applications.
    Dalin Di, Yanyan Zhang, Haixia Li, Qingxiang Zhang, Yuxia Li.
      Central memory T (TCM) cells are a cornerstone of the adaptive immune system, serving as a long-lived, self-renewing stem-like population that provides durable immunological protection. Primarily residing in secondary lymphoid organs, TCM cells are characterised by robust proliferative potential, multipotent differentiation capacity, and metabolic reliance on oxidative phosphorylation. These attributes are crucial for mediating rapid and effective secondary immune responses.Recent advances have elucidated the complex molecular circuitry governing TCM cells' fate decisions, focusing on the transcription factor networks and epigenetic modifications that preserve their characteristic stemness. In the context of disease, TCM cells play a dual role: they are a vital source of effector cells for combating infections and malignancies, yet they can also contribute to the chronic inflammation that drives autoimmune disorders including systemic lupus erythematosus, multiple sclerosis, systemic sclerosis, and Sjögren's disease.This functional dichotomy underlies their considerable clinical significance. Notably, TCM cells represent a preferred cellular source for chimeric antigen receptor T (CAR-T) cell therapy in both oncology and emerging autoimmune indications, serve as a predictive biomarker for the efficacy of immune checkpoint inhibitors, and act as a key indicator of vaccine effectiveness.This review comprehensively examines TCM cells, covering their biological features, developmental mechanisms, and recent clinical applications in cancer immunotherapy, autoimmune diseases, and cellular therapies, while outlining future therapeutic directions.
    DOI:  https://doi.org/10.55563/clinexprheumatol/0bkrx5
  25. bioRxiv. 2026 Mar 01. pii: 2026.02.26.708260. [Epub ahead of print]
    CD8 + T cells are primed by cDC1 and exacerbate tau-mediated neurodegeneration.
    Hao Hu, Peter Bor-Chian Lin, Carisa Zeng, Prabal Sharma, Yongyi Li, Hong Jiang, Jonathan Nulman, Ray A Ohara, Tong Wu, Shasha Li, Wayne M Yokoyama, Maxim N Artyomov, Kenneth M Murphy, Jason D Ulrich, David M Holtzman.
      There are changes in adaptive immunity in Alzheimer's disease (AD) and increases in activated CD8 + T cells in brain correlate with tau pathology 1-3 . However, which cells mediate T cell priming in tau-mediated neurodegeneration remains unclear. In different conditions such as cancer, viral infections, and autoimmune diseases outside the CNS, conventional type-1 dendritic cells (cDC1) perform antigen cross-presentation to prime CD8 + T cells 4,5 . We demonstrate that tauopathy mice deficient in cDC1 are markedly protected against tau-mediated neurodegeneration and display a selective decrease in brain CD8 + T cell infiltration and glial reactivity. The remaining CD8 + T cells showed an antigen inexperienced status with less clonal expansion, indicating suboptimal T cell priming. We confirm that brain derived antigens are presented in secondary lymphoid tissues to prime CD8 + T cells. Our study identifies cDC1 cells as critical for CD8 + T cell priming outside the CNS. This priming is required for a large increase of activated CD8 + T cells in the brain which promotes tau-mediated neurodegeneration.
    DOI:  https://doi.org/10.64898/2026.02.26.708260
  26. Curr Issues Mol Biol. 2026 Mar 16. pii: 315. [Epub ahead of print]48(3):
    American Ginseng (Panax quinquefolius) Extracts (G1899) Ameliorate Immunosenescence via Regulation of T Cell Populations and Aging-Related Proteins in a Mouse Model Induced by D-Galactose and Tert-Butyl Hydroperoxide.
    Ji-Hye Park, Jaehoon Lee, Chang Hwan Lee, Sun Hee Hyun, Seung-Ho Lee.
      Immunosenescence is characterized by an age-associated decline in immune function, particularly involving T-cell dysfunction, which increases susceptibility to infections and chronic diseases. This study investigated the anti-aging and immunomodulatory effects of American ginseng extract (G1899) using in vitro and in vivo models of aging. Cellular senescence was induced in HepG2 cells by D-galactose treatment, followed by exposure to G1899 (20 and 100 μg/mL). Senescence-associated markers were assessed to evaluate cellular aging. An aging mouse model was established in male C57BL/6 mice through intraperitoneal administration of D-galactose (500 mg/kg) and tert-butyl hydroperoxide (0.4 mmol/kg), and G1899 was orally administered at 400 mg/kg. Thymic immune cell subsets and aging-related protein expression were analyzed using flow cytometry and Western blotting. G1899 significantly reduced p21 expression and senescence-associated β-galactosidase activity in senescent HepG2 cells. In aging-induced mice, G1899 restored CD4+ and CD8+ T-cell populations, normalized naïve T-cell levels, and reduced anergic CD28-negative T cells. Furthermore, G1899 regulated the expression of key aging-related proteins, including FOXO1, Sirt1, p53, and CD38. These findings demonstrate that G1899 attenuates age-related immune alterations by restoring thymic T-cell homeostasis and regulating aging-associated molecular pathways.
    Keywords:  American ginseng; D-galactose; Sirt1; T cells; aging; immunosenescence
    DOI:  https://doi.org/10.3390/cimb48030315
  27. Metabolites. 2026 Mar 15. pii: 195. [Epub ahead of print]16(3):
    NHE1-Mediated Metabolic Reprogramming in Cancer.
    Majd A Al-Hamaly, Beau R Forester, Jessica S Blackburn.
      The sodium-hydrogen exchanger-1 (NHE1) is a ubiquitously expressed transmembrane transporter that plays a central role in maintaining intracellular pH homeostasis and supporting normal cellular function. In cancer, NHE1 is overexpressed in many tumor types and has been associated with increased cancer cell metastasis and proliferation. Beyond these established roles, emerging evidence implicates NHE1 as a regulator of cancer cell metabolism. By driving intracellular alkalinization and shaping the tumor microenvironment, NHE1 influences metabolic pathway activity, mitochondrial function, redox balance, and cellular stress responses. In this review, we synthesize current evidence linking NHE1 dysregulation to metabolic reprogramming in cancer, with a focus on mitochondrial metabolism, glycolytic flux, lysosomal biology, and reactive oxygen species-associated stress pathways. We further evaluate pharmacological strategies targeting NHE1, emphasizing their metabolic consequences, translational potential, and the challenges that have limited clinical application to date. Collectively, this review highlights NHE1 as a potential integrator of ion transport and metabolic control in cancer and discusses how targeting NHE1-driven metabolic programs may support the development of novel therapeutic strategies.
    Keywords:  NHE1; OXPHOS; cancer metabolism; ion exchangers; mitochondria; pH regulation
    DOI:  https://doi.org/10.3390/metabo16030195
  28. Cell Rep Methods. 2026 Mar 26. pii: S2667-2375(26)00043-3. [Epub ahead of print] 101343
    Single-cell assessment of iron content in primary human T cells using laser ablation inductively coupled plasma mass spectrometry.
    Diana M Carp, Piotr Golda, Alexander Griffiths, Katie Flaherty, Alexander Morrell, Anna Schurich.
      Transition metals, such as iron, support vital metabolic and signaling functions in immune cells. Cellular iron concentrations are tightly controlled. In T cells, both iron deficiency and iron overload have been linked to immune dysfunction. Homeostatic iron concentrations in T cells, and changes that occur during T cell activation, remain poorly understood due to difficulty of accurately measuring iron content in single cells, especially in small cells. Here, we describe the use of laser ablation inductively coupled plasma mass spectrometry (LA-ICP-MS) to accurately quantify the total amount of endogenous iron in individual primary human T cells. Our technique allows for targeted selection of single cells and reproducible quantification of iron at femtogram level. Our findings reveal that iron levels in resting T cells were similar across human donors. In contrast, T cell activation leads to diverse patterns between individual cells and donors, indicating specialized needs during differentiation.
    Keywords:  CP: biotechnology; CP: immunology; ICP-MS; LA-ICP-MS; T cells; human donors; iron metabolism; iron quantification; metalloimmunology; single-cell analysis; single-cell metallomics
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101343
  29. Cell Rep. 2026 Mar 20. pii: S2211-1247(26)00227-5. [Epub ahead of print]45(4): 117149
    Subversion of kynurenine-induced AHR activation in CD8 T cells by kynureninase-expressing antigen-presenting cells.
    Michael A Giacomantonio, Vishnu Vijay Vijayan, Preethi G Nair, Gopal P Pathak, Barry E Kennedy, Joao A Paulo, Teresa McMillen, Anurag Banerjee, Vishnupriyan Kumar, Mukhayyo Sultonova, Tayah Sommer, Nisha Owens, Unnikrishnan Babukuttan Sheela, Jawairia Atif, Sonya A MacParland, Steven P Gygi, J Patrick Murphy, Shashi Gujar.
      Kynurenine, an intermediate metabolite of tryptophan metabolism, suppresses the antitumor activity of CD8+ T cells by activating the aryl hydrocarbon receptor (AHR). Its role in adaptive immunity is poorly understood. Outside the liver, kynurenine is mainly produced by indoleamine 2,3-dioxygenase 1 (IDO1) and further degraded by kynureninase (KYNU). This report shows that KYNU is predominantly expressed in human and mouse antigen-presenting cells (APCs) in vivo, GM-CSF-differentiated macrophages and dendritic cells in vitro, and alveolar macrophages collected in situ, and is functionally active in breaking down kynurenine into catabolic products without contributing toward de novo NAD+ synthesis. Importantly, while CD8+ T cells uptake kynurenine, they lack active KYNU, leading to AHR-dependent immunosuppression. However, KYNU-expressing APCs can deplete extracellular kynurenine, prevent AHR activation, and restore IFN-γ production in CD8+ T cells. This highlights the importance of KYNU-expressing APCs in combating kynurenine-induced immune suppression against tumors.
    Keywords:  CD8(+) T cells; CP: cancer; CP: metabolism; GM-CSF; IDO1; KYNU; alveolar macrophages; antigen-presenting cells; antitumor immunity; bone marrow; kynureninase; kynurenine pathway; macrophage metabolism; tryptophan catabolism
    DOI:  https://doi.org/10.1016/j.celrep.2026.117149
  30. Cancer Commun (Lond). 2026 ;46 0021
    TOPK Suppresses the CD8+ T Cell Antitumor Immunity via Modulation of IRF5 Expression.
    Nianke Zang, Jinfeng Gan, Ye Chen, Zheng Huang, Chichu Xie, Junlong Dang, Changyuan Huang, Linjie Yang, Xuelian Chen, Guangli Rong, Jianbo Sun, Yiming Shao, Julie Wang, Guangying Qi, Yu Liu, Song Guo Zheng.
      Background: T-LAK cell-originated protein kinase (TOPK), a serine/threonine kinase, is aberrantly overexpressed in human tumors and promotes malignant proliferation. Melanoma is a highly immunogenic tumor in which CD8+ T cell-mediated cytotoxicity is usually less effective in tumor control and responsive to immune checkpoint blockade. It is unclear whether the expression and functional characterization of TOPK within the immune cells affect the tumor microenvironment (TME) in patients with melanoma. This study aims to elucidate the expression pattern and immunoregulatory function of TOPK in CD8+ T lymphocytes during antitumor responses. Methods: Public single-cell RNA-sequencing (scRNA-seq) dataset analysis and flow cytometry assessed TOPK in tumor-infiltrating CD8+ T cells from patients with melanoma. Genetic deletion and pharmacological inhibition of TOPK using HI-TOPK-032 tested T cell-mediated melanoma control. Flow cytometry and tumor cell coculture killing assays measured effector release and target-cell apoptosis. Mechanistic analyses included assessment of interferon regulatory factor 5 (IRF5) expression, together with combination therapy using a programmed cell death protein 1 (PD-1)-blocking antibody in vivo. scRNA-seq of tumor-infiltrating lymphocytes (TILs) from Topk fl/fl and Cd8 Cre Topk fl/fl mice was also performed to define TOPK-dependent immune programs within the melanoma TME. Results: Single-cell transcriptomes identified a TOPK+ subset of tumor-infiltrating CD8+ T cells in melanoma, which was higher than that in normal lymph nodes (LNs), and exhibited suppressed cytotoxic and cytokine programs. CD8+ T cell-specific Topk deletion increased granzyme B (GzmB), tumor necrosis factor-α (TNF-α), and interferon-γ (IFN-γ) secretion and improved tumor control. TOPK-deficient CD8+ T cells showed elevated activation-associated signaling pathways and immune effector gene expression. In murine TIL scRNA-seq, Cd8 Cre Topk fl/fl tumors exhibited increased effector and activation programs, reduced exhaustion and dysfunction programs, and enhanced immune crosstalk in the TME. Mechanistically, TOPK suppressed IRF5 expression and HI-TOPK-032 restored CD8+ T cell cytotoxicity in vitro and, with anti-PD-1, further inhibited tumor growth and increased intratumoral cytokine production. In human CD8+ T cells, enforced TOPK expression impaired cytotoxicity and cytokine secretion, reversed by IRF5 coexpression. Conclusions: These findings establish TOPK as the immune checkpoint limiting CD8+ T cell functionality in tumors and indicate the potential of TOPK inhibition as a strategy to augment T cell-based immunotherapies.
    DOI:  https://doi.org/10.34133/cancomm.0021
  31. Biomolecules. 2026 03 02. pii: 374. [Epub ahead of print]16(3):
    Cell-Intrinsic Type I Interferon Signaling as a Pleiotropic Orchestrator of CD4 T Cell Immunity.
    Eugene Baffoe, Adhithya Aaron Anand, K Kai McKinstry.
      Type I interferons (IFN-I) are pleiotropic cytokines best known for their antiviral impacts. However, they are known to also impact immune responses outside of viral infection through directly signaling many populations of innate and adaptive immune cells. Here, we focus on the complex body of findings from viral, bacterial, and parasitic infection models, cancer and autoimmunity studies, as well as in vitro experiments using human and murine T cells, demonstrating that IFN-I can be directly sensed by CD4 T cells. Such signaling has been shown to influence many central aspects of antigen-specific CD4 T cell responses, including proliferation, apoptosis, effector subset differentiation, and memory formation. These effects are frequently divergent and sometimes opposing, likely reflecting how differences in variables related to the IFN-I signal, overall inflammatory milieu, and the CD4 T cell integrate to shape outcomes. Indeed, we discuss findings supporting a framework in which dynamic engagement of canonical and non-canonical signaling pathways downstream of IFN-I, which are contingent on a cell's activation state, play a key role in determining whether and how IFN-I promotes, restrains, or otherwise reprograms CD4 T cell fates. Together, these observations highlight the impressive scope of regulation that IFN-I signals to CD4 T cells can exert, parallel to its actions on other immune and non-immune cell types. They also suggest that harnessing such signaling could offer powerful therapeutic strategies to shape CD4 T cell immunity in diverse context-dependent situations.
    Keywords:  CD4 T cell; STAT1; STAT4; Th subsets; memory; type I IFN
    DOI:  https://doi.org/10.3390/biom16030374
  32. Cells. 2026 Mar 13. pii: 517. [Epub ahead of print]15(6):
    Mitochondrial Quality Control and Metabolic Reprogramming in Hepatocellular Carcinoma: Implications for Immunotherapy and Treatment Resistance.
    Yusra Zarlashat, Anna Picca.
      Hepatocellular carcinoma (HCC) is a leading cause of cancer death, characterized by poor prognosis in advanced stages despite available therapies. Dysfunctional mitochondrial can initiate both tumor progression and antitumor immunity. Altered mitochondrial quality control mechanisms, including dynamics, biogenesis, and degradation, contribute to mitochondrial decline supporting hepatocarcinogenesis and tumor survival. Within the immunosuppressive tumor microenvironment, HCC cells shift their metabolism toward glycolysis, which reduces nutrient availability and triggers mitochondrial dysfunction in infiltrating immune cells, leading to T-cell exhaustion and weakened cytotoxic activity. Herein, we discuss how immune checkpoint inhibitors may respond to this exhaustion. While most findings showing that these therapies partially restore mitochondrial bioenergetics in T cells have been conducted in preclinical studies, direct clinical evidence in HCC patients remains limited. By combining current knowledge on mitochondrial metabolism, immune escape, and treatment resistance, we discuss how targeting mitochondrial pathways may help improve immunotherapy responses and support new combination treatment approaches against HCC.
    Keywords:  T-cell exhaustion; immune evasion; immunotherapy; metabolic reprogramming; mitochondrial biogenesis; mitochondrial dynamics; mitophagy; tumor microenvironment
    DOI:  https://doi.org/10.3390/cells15060517
  33. Dev Cell. 2026 Mar 26. pii: S1534-5807(26)00085-7. [Epub ahead of print]
    Unleashing T cell surveillance for the eradication of quiescent persister tumor cells resistant to neoadjuvant chemotherapy.
    Haigang Geng, Hongye Wang, Chuanjie Zhang, Yangyang Zhou, Yiqing Zhong, Zhenhua Zhu, Zhaorong Wu, Tangansu Zhang, Nuo Xu, Zhongyi Dong, Haoyu Zhang, Qian Li, Yan Li, Xiangyu Tang, Xifu Cheng, Xiang Xia, Zizhen Zhang, Bo Zhai, Zhigang Zheng, Qing Li, Chen Yang, Chunchao Zhu.
      Although neoadjuvant chemotherapy (NAC) has shown efficacy in reducing tumor burden in colorectal cancer (CRC), its impact on long-term patient outcomes remains limited. Here, we identify quiescent persister tumor cells (PTCs) as a critical determinant of therapeutic failure. Elevated PTC abundance correlates with poor long-term prognosis, even in patients exhibiting an initial response to treatment. Quiescent PTCs possess aggressive stem-like traits and orchestrate an immunosuppressive microenvironment characterized by CD96+CD8+ T cell infiltration in an orthotopic CRC mouse model. CD96 depletion diverts CD8+ T cells from an exhaustion trajectory and promotes memory-like phenotypes through enhanced mitochondrial function. Consistently, anti-CD96 therapy effectively eliminates PTCs in preclinical models. We also engineered epithelial cell adhesion molecule (EpCAM)-targeted human chimeric antigen receptor (CAR)-T cells deficient in CD96 expression, which robustly target PTCs and demonstrate remarkable therapeutic potential against CRC. Overall, our study uncovers CD96 as a previously unrecognized axis of vulnerability within the PTC-driven microenvironment, offering a promising avenue to enhance CRC therapeutic outcomes.
    Keywords:  CD96; colorectal cancer; neoadjuvant chemotherapy; persister tumor cells; quiescence
    DOI:  https://doi.org/10.1016/j.devcel.2026.02.020
  34. bioRxiv. 2026 Mar 02. pii: 2026.02.28.707294. [Epub ahead of print]
    Aberrant oxidative metabolism selects for TET2 -deficient hematopoietic stem and progenitor cells.
    Katia E Niño, Vera Adema, Alyx E Gray, Courtney M Cowan, Wolfgang E Schleicher, Mohsen Hosseini, Sierra N Bennett, Sweta B Patel, Steven Moreira, Etienne Danis, Feiyang Ma, Hsin-Ying Lin, Tracy N Young, Colin A Anderson, Devyani Sharma, Angelica Varesi, Marie-Dominique Filippi, Keisuke Ito, Meelad M Dawlaty, Gang Huang, Julie A Reisz, Stephanie Z Xie, Steven M Chan, Lin Tan, Guillermo Garcia-Manero, Kelly Chien, Irene Gañan Gomez, Angelo D'Alessandro, Simona Colla, Eric M Pietras.
      The mechanism(s) driving selective expansion of mutant hematopoietic stem and progenitor cells (HSPC) in clonal hematopoiesis (CH) are incompletely understood. Here, we address the role of metabolism in selection for HSPC with loss of function mutations in TET2 . Loss of Tet2 in murine HSPC triggers overexpression of glycolysis and oxidative phosphorylation genes and increased oxidative metabolism via an enlarged mitochondrial network. However, Tet2 -deficient HSPC maintain a normal redox state. Strikingly, compound loss of the rate-limiting pentose phosphate pathway (PPP) enzyme glucose-6-phosphate dehydrogenase (G6PD) triggers increased reactive oxygen species and impairs the fitness of Tet2 -deficient HSPC. We find that aberrant oxidative metabolism is also a feature of HSPC in human CH and clonal cytopenia of unknown significance (CCUS). Overall, our data point to aberrant metabolism as a critical and conserved driver of selection in TET2 -deficient CH and identify the PPP as a crucial compensatory pathway needed to maintain their selective advantage.
    Statement of Significance: This study identifies oxidative metabolism as a critical driver of selection for TET2 -deficient HSPC in clonal hematopoiesis (CH). It also demonstrates that cellular redox state is a vulnerability that impairs their fitness. These insights establish targetable metabolic pathway(s) that could be exploited in the setting of TET2 mutant CH.
    DOI:  https://doi.org/10.64898/2026.02.28.707294
  35. Blood. 2026 Mar 24. pii: blood.2025031552. [Epub ahead of print]
    Iron overload damages mitochondria and induces metabolic rewiring of hematopoietic stem cells towards glycolysis.
    Silvia Sighinolfi, Laura Cassina, Maria Rosa Lidonnici, Stefano Beretta, Davide Stefanoni, Mariangela Storto, Christina Mayerhofer, Trine A Kristiansen, David T Scadden, Ivan Merelli, Alessandra Boletta, Annamaria Aprile, Giuliana Ferrari.
      Iron is an essential element for most cellular processes and recent evidence highlighted its role in regulating the function of hematopoietic stem cells (HSCs). Abnormal iron levels impact HSC quiescence and self-renewal, however, the mechanism by which iron overload (IO) influences HSC function is still unknown. Here, we show that intracellular IO impairs mitochondrial fitness and bioenergetics, inducing metabolic rewiring. In thalassemic mice, as a model of chronic IO, HSCs accumulate mitochondria with elevated reactive oxygen species (mtROS), low membrane potential and reduced oxidative phosphorylation (OXPHOS). Mitochondrial defects are confirmed in other two models of IO, sickle cell disease and iron-loaded wild-type mice, and in vivo iron reduction rescues HSC mitochondria. IO HSCs are highly proliferating and in presence of damaged mitochondria rely on glycolysis for energy production. Notably, restoration of mitochondrial function by targeting in vivo mtROS improved the quiescence and self-renewal of IO HSCs. Our results unravel the critical interplay between iron, ROS and mitochondrial activity in HSCs, revealing that IO shapes HSC metabolic programs.
    DOI:  https://doi.org/10.1182/blood.2025031552
  36. Antioxidants (Basel). 2026 Mar 11. pii: 353. [Epub ahead of print]15(3):
    Copper Dyshomeostasis, Redox Buffering and Immune Aging Converge on Cuproptosis in Age-Related Diseases.
    Yubin Jin, Keyu Lu, Yang Yang.
      Cuproptosis is a copper-dependent form of regulated cell death that is triggered when intracellular copper handling is perturbed and mitochondrial metabolism becomes the primary site of damage. Aging provides a biological context for this process because copper trafficking shifts, mitochondrial quality control and proteostasis decline, and immune function is remodeled toward immunosenescence with persistent low-grade inflammation. These age-associated changes can weaken antioxidant buffering, reshape labile copper pools, and lower the threshold at which copper stress is converted into mitochondrial proteotoxic injury. In parallel, inflammaging-related cytokines and NF-κB programs can alter copper import, export, and sequestration, while impaired efferocytosis prolongs danger signaling, creating feedforward loops that sustain tissue injury. In this review, we summarize the molecular features that distinguish cuproptosis from other death programs and discuss how redox buffering capacity, copper transport machinery, and mitochondrial metabolic state jointly determine cuproptosis sensitivity during aging. We then examine disease contexts in which these pathways are plausibly relevant, including hereditary copper-handling disorders and age-related neurodegenerative, cardiovascular, metabolic, and musculoskeletal disorders. Finally, we discuss key knowledge gaps and experimental priorities for interpreting cuproptosis-related signals in aged tissues, with emphasis on how copper handling, mitochondrial state, and immune remodeling jointly shape disease phenotypes.
    Keywords:  copper homeostasis; cuproptosis; glutathione; immunosenescence; inflammaging; iron sulfur clusters; mitochondrial metabolism; oxidative stress; protein lipoylation; redox buffering
    DOI:  https://doi.org/10.3390/antiox15030353
  37. Nat Rev Immunol. 2026 Mar 25.
    T cell lymphomas: cancers of aberrant immune synapse signalling.
    Peter A Tauber, Jürgen Ruland.
      Peripheral T cell lymphomas (PTCLs) are a diverse group of aggressive malignancies that arise from mature, post-thymic T cells. Recent genomic and mechanistic studies reveal that these cancers frequently 'hijack' signalling pathways that normally govern T cell activation at the immunological synapse. Specifically, numerous gain-of-function alterations in TCR proximal regulators and mediators of antigen-induced NF-κB activation, as well as mutations or overexpression of co-stimulatory receptors and dysregulated cytokine receptor signalling, promote the constitutive proliferation and survival of malignant clones. Conversely, loss-of-function mutations in PDCD1 or disruption of PD1-mediated inhibitory control, coupled with altered metabolic and epigenetic reprogramming, have emerged as a major tumour-suppressor mechanism in PTCL pathogenesis. This framework conceptualizes PTCLs as 'cancers of aberrant immune synapse signalling pathways' and posits that genetic dissection of PTCL pathogenesis can uncover fundamental aspects of T cell biology to guide the design of safer, more effective next-generation T cell therapies.
    DOI:  https://doi.org/10.1038/s41577-026-01283-5
  38. Int Immunopharmacol. 2026 Mar 23. pii: S1567-5769(26)00392-9. [Epub ahead of print]177 116547
    The pivotal role of metabolism in shaping tumor-associated macrophages phenotype and function.
    Mei Jun, Tiantian Li, Yilin Shi, Hang Yin, Wenjie Wu, Xinmin Dong, Xigetu He, Xiong Lai.
      Tumor progression is critically shaped by the dynamic interplay between tumor cells and the tumor microenvironment (TME). The TME harbors a diverse array of immune cells, encompassing T cell, B cell, NK cell and macrophages. Among these, TAMs profoundly shape tumor growth and metastasis by interacting with tumor cells and other immune cells. To adapt to the varied immune and metabolic cues in the TME, they undergo dynamic metabolic reprogramming, which recent advances have shown to involve extensive remodeling of glucose, lipid, and amino acid metabolism, along with the tricarboxylic acid cycle. However, critical knowledge gaps remain regarding the cellular heterogeneity of TAM metabolic reprogramming, divergent metabolic signatures across TAM subsets, and context-dependent variations in metabolic rewiring among different cancer types. However, the mechanisms by which these metabolic alterations translate into distinct functional phenotypes and shape the immune landscape of the TME remain poorly defined. This review systematically synthesizes the current knowledge on how metabolic remodeling in TAMs regulates their polarization and pro-tumor functions. We specifically focus on delineating the heterogeneity of TAM metabolic features across tumor types and subsets and discuss the implications of these metabolic variations for TAM-mediated immunosuppression. Furthermore, we summarize the representative therapeutic agents targeting key metabolic nodes in TAMs. By integrating emerging insights into TAM metabolism and associated pharmacologic interventions, this review aims to identify key unanswered questions and provide a theoretical framework for developing precision immunotherapies that target TAM metabolic nodes without compromising anti-tumor immunity.
    Keywords:  Amino acid metabolism; Glucose metabolism; Lipid metabolism; Metabolic reprogramming; Tricarboxylic acid cycle; Tumor-associated macrophages
    DOI:  https://doi.org/10.1016/j.intimp.2026.116547
  39. bioRxiv. 2026 Mar 17. pii: 2026.03.10.710574. [Epub ahead of print]
    Therapeutic scheduling of WEE1 inhibition preserves T cell function and promotes immune control of HPV⁺ tumors.
    Ying Liu, Zhiheng Zhang, Yanshan Tao, Lovely Rahgav, Sophie Gray-Gaillard, Yasser Hussaini, Meijie Pan, Justine Shamber, Jeff Kwak, Simone L Park, Jessica Cramer, Regina Stoltz, Joseph Patria, Jherek Swanger, Kathryn Liu, Malay Kumar Sannigrahi, A McGarry Houghton, Cristina P Rodriguez, Ryan M Carey, Robert Brody, Karthik Rajasekaran, Gregory Weinstein, Gerald P Linette, Beatriz M Carreno, Mark M Painter, E John Wherry, Bruce Clurman, Devraj Basu, Ahmed Diab.
      Human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV⁺ OPC) is driven by viral E6 and E7 oncoproteins, which disrupt G1 checkpoint control and impose selective dependency on WEE1-mediated G2/M regulation. While this vulnerability confers sensitivity to WEE1 inhibition, its immunologic consequences remain poorly defined, and the challenge of eliciting antitumor immunity without compromising immune fitness has limited clinical translation. Here, we show that WEE1 inhibition elicits durable antitumor immunity in immunocompetent models of HPV⁺ OPC. Using murine and human preclinical systems, we demonstrate that the WEE1 inhibitor azenosertib (ZN-c3) mediates tumor control through both cell-autonomous cytotoxicity and immune-dependent mechanisms requiring T cells and conventional dendritic cells. Mechanistically, HPV⁺ tumor cells are deficient in STING signaling and fail to mount canonical type I interferon responses. Instead, tumor cell-intrinsic cGAS drives immune activation through STING-competent host cells within the tumor microenvironment, revealing a non-cell-autonomous relay that circumvents viral immune evasion. Intermittent WEE1 inhibition preserves T cell fitness while maintaining antitumor efficacy, and mice achieving complete responses develop immunologic memory capable of rejecting tumor rechallenge. These findings establish intermittent WEE1 inhibition as an immune-permissive therapeutic strategy that enables antigen-specific T cell responses in HPV-driven malignancies and provides a mechanistic rationale for combination with immunotherapy.
    DOI:  https://doi.org/10.64898/2026.03.10.710574
  40. Cancer Gene Ther. 2026 Mar 24.
    The TCR in CAR T cell therapy: use it or lose it?
    Olivia Liseth, Richard Vile.
      Chimeric antigen receptor (CAR) T cell therapy has become an indispensable immunotherapy for the treatment of some hematologic cancers, but still faces numerous challenges in the form of antigen escape, variable patient responses, toxicities, limited CAR T cell persistence, and high cost, particularly against solid tumors. This Review discusses the potential role of the endogenous T cell receptor (TCR) as either a hindrance or partner to CAR T cell function. Specifically, we discuss the differences and similarities between CAR and TCR structure and function, findings supporting the value of TCR elimination in CAR T cells, and, in contrast, data in support of retaining and utilizing the endogenous TCR in CAR T cell therapy. We make the case that, while TCR-knockout systems may improve aspects such as the universality, cost, and CAR expression of CAR therapies, the endogenous TCR continues to play a significant role in maintaining CAR T cell persistence and can be used to augment CAR T cell therapeutic phenotypes. Overall, we highlight the uncertainties that persist within the field of CAR T cell therapy and outline emerging evidence and directions regarding the CAR T cell TCR that have the potential to transform patient outcomes.
    DOI:  https://doi.org/10.1038/s41417-026-01018-7
  41. J Nanobiotechnology. 2026 Mar 27.
    Targeted inhibition of ITK activity with anti-CD3 antibody-modified calcium silicate nanoparticles loaded with novel 7H-Pyrrolo[2,3-d]pyrimidine derivatives for treating aplastic anemia.
    Xia Liu, Hui Li, Ningning Shan, Bingxin Guan, Yang Jiang, Chengyun Zheng, Leisheng Zhang, Dexiao Kong.
      Aplastic anemia (AA) is a debilitating disorder marked by bone marrow failure, frequently associated with dysregulated T cell activity. The present study explored the therapeutic potential of anti-CD3 antibody-modified calcium silicate nanoparticles loaded with novel   7H-pyrrolo[2,3-d]pyrimidine derivatives (antiCD3-pCaSiNP@NPDP) for AA treatment. Whole-transcriptome sequencing and bioinformatics analysis identified interleukin-2-inducible T-cell kinase (ITK) as a critical regulator of T cell function in AA. In vitro experiments demonstrated that ITK enhances T cell proliferation and promotes differentiation toward inflammatory subsets, thereby contributing to disease progression. The newly developed NPDP derivatives effectively inhibited ITK activity. Targeted delivery of NPDP via antiCD3-pCaSiNP nanoparticles selectively suppressed ITK expression in T cells, resulting in reduced inflammatory T cell proliferation and increased regulatory T cell populations. In an AA mouse model, administration of antiCD3-pCaSiNP@NPDP nanoparticles markedly improved hematopoietic recovery and immune balance. The findings indicate that nanoparticle-mediated ITK inhibition represents a promising therapeutic strategy for restoring immune and bone marrow function in AA.
    Keywords:  Aplastic Anemia; Calcium Silicate Nanoparticles; Immune Regulation; Interleukin-2-Inducible T-Cell Kinase; T Cell Regulation
    DOI:  https://doi.org/10.1186/s12951-026-04276-7
  42. Cell Death Dis. 2026 Mar 23.
    SIRT1 deficiency promotes age-related heart failure through enhancing ferroptosis via GATA4-HADHA-GPX4 axis.
    Yu Duan, Yingchun Luo, Xuejie Han, Hui Yu, Hanwen Liu, Yun Zhou, Yunlong Gao, Qian Xu, Ying Wei, Ruoxin Min, Yong Hong, Xuanrui Ji, Haibo Jia, Yue Li, Yun Zhang.
      Aging is a major contributor to the escalating prevalence of heart failure (HF). Ferroptosis has been implicated in age-related disorders and cardiovascular diseases. The role of ferroptosis in age-related HF remains unclear. Here, we show that aged rats exhibit impaired cardiac function accompanied by hallmark features of ferroptosis, including reduced glutathione peroxidase 4 (GPX4) expression and excessive lipid peroxidation. Consistently, cardiomyocyte-specific GPX4 knockout mice develop exacerbated cardiac ferroptosis and pronounced cardiac dysfunction. Iron overload further aggravates ferroptotic injury and cardiac dysfunction in aged rats, whereas pharmacological inhibition of ferroptosis markedly alleviates these effects. Conversely, cardiomyocyte-specific overexpression of GPX4 via rAAV9 attenuates ferroptosis and preserves cardiac function in D-galactose-induced aging mice. Proteomic analysis identifies hydroxyacyl-CoA dehydrogenase subunit A (HADHA) as a key protein markedly downregulated in aging hearts, particularly under iron overload. Mechanistically, HADHA deficiency induces mitochondrial dysfunction and excessive reactive oxygen species production, leading to glutathione depletion, GPX4 suppression, and subsequent ferroptosis. Accordingly, cardiomyocyte-specific knockdown of HADHA in young mice recapitulates ferroptosis-associated cardiac remodeling, which is reversed by ferrostatin-1 treatment. Furthermore, we identify SIRT1 (sirtuin 1) as an upstream regulator of HADHA during cardiac aging. Reduced SIRT1 expression in aging hearts suppresses HADHA transcription through inhibition of GATA4. Importantly, both cardiomyocyte-specific SIRT1 overexpression via rAAV9 in D-galactose-induced aging mice and pharmacological SIRT1 activation by resveratrol in aging rats restore HADHA expression, suppress ferroptosis, and protect against HF. Collectively, these findings establish ferroptosis as a critical contributor to age-related HF and identify the SIRT1-GATA4-HADHA axis as a potential therapeutic target.
    DOI:  https://doi.org/10.1038/s41419-026-08634-z
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