bims-imseme 2026-05-03 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–05–03
forty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Testing the mettle of RNA methylation in T cell exhaustion.
Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.
Phospho-enol pyruvate carboxykinase inhibition limits effector function in inflammatory T cells.
Postprandial lipid metabolism durably enhances T cell immunity.
Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity.
Lymphoid tissue chemokines limit priming duration to preserve CD8+ T cell functionality.
PTK6 promotes ferroptosis resistance and CD8+ T cell exhaustion in pancreatic tumors via reprogramming glucose and lipid metabolism.
Citraconate preserves T cell stemness and antitumor immunity.
Extracellular vesicles inherit lactate from aggregated MSCs to alleviate type 1 diabetes mellitus via H2S-induced CD8+ T cell exhaustion.
Serial vaccination expands and refines human CD4 + T cell memory.
Metabolic reprogramming of Th17/Treg imbalance in autoimmune thyroid diseases.
Vaccination rescues dysfunctional T cell therapy by amplifying rare stem-like antitumor CD8⁺ T cells.
Remodeling the Tumor Immune Microenvironment by Traditional Chinese Medicine: Mechanisms Focusing on TAM Polarization and CD8+ T Cell Exhaustion.
Macronutrient availability and immune cell responses.
T cell exhaustion: Next-generation target of autoimmune diseases?
CTL lymph node entrapment drives lymphopenia in severe influenza infection.
T Cell Immunosenescence in Inflammatory Skin Diseases: Pathogenesis and Therapeutic Targets.
Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function.
Newly isolated human-derived Lactobacillus fermentum strain stimulates IFN-γ-secreting CD8+ T cells for enhanced anti-cancer immunity.
Tet2 deficiency alters CD4+ T cell function and promotes T cell lymphoma with a TFH cell immunophenotype.
Peanut Procyanidin A Delays Hematopoietic Stem Cells Aging through Cox5a.
Gut-derived metabolic reprogramming drives immune aging and tissue degeneration.
Canonical WNT Ligands Produced by Regulatory T Cells Restrain Effector CD4 + T Cell Responses.
Deficiency of microRNA-10a in CD4+ T cells protects against intestinal infection through mitochondrial oxidation-IL-22 pathway.
Cytochrome P450 1B1 directs pathogenic Th17 cell generation and autoimmune disease by fine-tuning redox homeostasis and mitochondrial integrity.
An ICAM1-targeting chimeric costimulatory receptor mimics the immune synapse and enhances tumor-specific T cell function.
PD-1-targeted IL-15 mutein activates CD8+ and CD4+ T cells in infection and cancer.
Inflammaging and the role of micronutrients as immunomodulators: a pathway to healthy aging.
The immunoregulatory effect of short-chain fatty acids in type 2 diabetes mellitus.
Not so cold after all: tumor infiltrating CD8+ T cells in EBV-positive Burkitt lymphoma are quiescent, not exhausted.
Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function.
A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8 + T cell antitumor immunity.
Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse.
Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.
Mathematical modeling of immune counter-regulation predicts efficacy of fractionated CD8+ T cell dosing strategies.
TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.
Engineering fratricide-resistant CCR4/CD7 CAR T cells with enhanced safety and persistence for T cell malignancies.
Proteasome alteration between epithelial and hematopoietic cells facilitates positive selection of CD8 T cells.
Activation-gated, T cell-restricted silencing of Dapk1 enhances Bacille Calmette-Guérin-elicited protective CD4+ memory.
Class I HDAC inhibition enhances the stem-like memory properties of CRISPR-engineered CAR T cells in neuroblastoma.
Lactylation of HIF-1α at K172 drives HIF-1 complex assembly to promote hypoxia-induced immune evasion in esophageal squamous cell carcinoma.
Therapeutic targeting of BCL-2 during CART cell production augments potency through non-apoptotic adaptive changes.

J Exp Med. 2026 May 04. pii: e20260349. [Epub ahead of print]223(5):

Testing the mettle of RNA methylation in T cell exhaustion.

Cansu Yerinde, Debattama Rai Sen.

Song et al. (https://doi.org/10.1084/jem.20250424) identify Mettl8 as a regulator of progenitor exhausted CD8+ T cells, stabilizing Tcf7 transcripts and shaping chromatin programs. Mettl8 loss drives effector differentiation and improves tumor control, underscoring RNA methylation as a key layer of T cell fate regulation.

DOI: https://doi.org/10.1084/jem.20260349
Immunity. 2026 Apr 29. pii: S1074-7613(26)00144-5. [Epub ahead of print]

Metabolic and transcriptional plasticity supports CD8+ T cell resilience and anti-tumor immunity under nutrient stress.

Michael Scaglione, Montana Knight, Krittin Trihemasava, Kelly Rome, Anne-Sophie Archambault, Juhee Oh, Erin Tanaka, Elise Hall, Tran Ngoc Van Le, Caleb L Lines, Brian Goldspiel, Hossein Fazelinia, Clemence Queriault, Lucien Turner, Tanay Parnaik, Jimmy Xu, Morgan Brown, Oishi Bardhan, Jessie Axsom, Frederick C Bennett, Lynn A Spruce, Caroline Bartman, Clementina Mesaros, Ramon I Klein Geltink, Crystal S Conn, Will Bailis.

  CD8+ T cells need to function in complex environments with varied nutrient availability, including the tumor microenvironment and inflamed tissues. The mechanisms that allow CD8+ T cells to maintain immune function in these perturbed settings are poorly understood. Here, we show that CD8+ T cells adapt to nutrient stresses over time, reconfiguring gene-regulatory and metabolic networks to license functional recovery. Under acute stress, T cells reoriented translational programming, which limited nutrient demand and prioritized stress-sensitive metabolic and transcriptional responses. Within these responses, the transcription factors activating transcription factor 4 (ATF4) and CCAAT/enhancer-binding protein gamma (CEBPG) jointly established an adaptive metabolic program, promoting amino acid synthesis and uptake while maintaining mitochondrial metabolism. Despite diminished energetic capacity under environmental stress, this program sustained central carbon metabolism. This subsequently mitigated cellular dysfunction and potentiated anti-tumor immunity. Altogether, we demonstrate that biosynthetic plasticity via translational and metabolic reprioritization confers T cell resilience in unfavorable environments, offering potential strategies to enhance immunotherapies.

Keywords:  ATF4; CD8(+) T cells; CEBPG; GCN2; HRI; T cell exhaustion; T cells; amino acids; anti-tumor immunity; immunometabolism; integrated stress response; mTOR; nutrient stress; polysome profiling; stress adaptation; translation; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1016/j.immuni.2026.04.004
Front Immunol. 2026 ;17 1706167

Phospho-enol pyruvate carboxykinase inhibition limits effector function in inflammatory T cells.

Rebecca J Brownlie, Helen Carrasco Hope, David Wright, Graham P Cook, José C Perales, Robert J Salmond.

   Introduction: Following antigenic stimulation, T cells switch from a catabolic metabolic state maintained by low levels of nutrient uptake to an anabolic metabolism that sustains the biosynthetic and energetic demands of clonal expansion, differentiation, and effector function. Much progress has been made in understanding the transcriptional and enzymatic regulation of activated T cell metabolism. However, less is understood of the role for regulators of anaplerosis and cataplerosis such as phospho-enol pyruvate carboxykinases (PEPCK) in T cells.
Methods: Assessment of PEPCK expression in mouse T cells was performed. Pharmacological inhibitors were used to assess functional and metabolic roles for PEPCKs in T cell activation.
Results: We show that mitochondrial PEPCK (PEPCK-M) is upregulated following T cell activation, while cytosolic PEPCK-C was not detected. The PEPCK inhibitors limited CD8+ T cell cytotoxic capacity and both CD4+ and CD8+ T cell inflammatory cytokine production. The suppression of T cell effector functions by PEPCK inhibitors was associated with decreased maximal mitochondrial respiration.
Discussion: These data suggest that PEPCKs act to modulate mitochondrial metabolism, supporting effector function in T cells.

Keywords:  PEPCK; T cell; T cell activation; immunometabolism; phospho-enol pyruvate carboxykinases

DOI:  https://doi.org/10.3389/fimmu.2026.1706167
Nature. 2026 Apr 29.

Postprandial lipid metabolism durably enhances T cell immunity.

Alok Kumar, Dayana B Rivadeneira, Isha Mehta, Bingxian Xie, Rachel Cumberland, Supriya K Joshi, Jitendra S Kanshana, William G Gunn, Victoria Dean, Angelina Parise, Kristin Morder, Erica S Myers, Steven J Mullett, Richard T Cattley, Stacy L Gelhaus, Abigail E Overacre-Delgoffe, Jishnu Das, William F Hawse, Alison B Kohan, Greg M Delgoffe.

Although intrinsic metabolic pathways have critical roles in T cell function1,2, systemic nutrient availability is in constant flux. Yet, how postprandial metabolism affects T cell fate has been less studied. Here we show that the short-term nutritional state of an individual has marked effects on T cell immunity. Human or murine T cells from fed hosts had higher metabolic capacity than those from fasted hosts, and this increase in capacity persisted after activation and expansion in vitro or in vivo. Triglyceride-rich chylomicrons in serum were drivers of postprandial immunometabolic reprogramming, and chylomicrons primed mTORC1-dependent translation ex vivo and after activation, which markedly enhanced effector function after priming. Human postprandial CAR-T cells manufactured from the same donor showed a therapeutic advantage over T cells collected while individuals were fasted. Thus, postprandial metabolism imparts durable metabolic and functional advantages to T cells, highlighting the importance of considering nutritional status in immunological analysis, vaccination and generation of cellular therapies.

DOI: https://doi.org/10.1038/s41586-026-10432-8
Immunity. 2026 Apr 27. pii: S1074-7613(26)00140-8. [Epub ahead of print]

Krüppel-like factor 2 programs early exhausted T cell states and restrains antiviral immunity.

Shengjun Geng, Zifeng Li, Wenhao Li, Huiqing Liang, Fan Xu, Leilei Zhang, Wei Zhang, Shengyong Tao, Yanhan Wang, Yurui Zhou, Shijie Luo, Xing Lei, Hailang Li, Wei-Feng Huang, Meixia Che, Wen-Hsien Liu, Jialiang Huang, Tianying Zhang, Kejia Wang, Nengming Xiao, Kairui Mao, Yajun Jiang, Hongling Huang.

  A key challenge in improving T cell-mediated immunotherapies is defining the factors that regulate functional versus exhausted T cell fates. Through multi-round in vivo CRISPR screens in chronic lymphocytic choriomeningitis virus Clone 13 (LCMV Cl13) infection and transcription factor (TF) benchmarking, we identified Krüppel-like factor 2 (KLF2) as a top TF driving CX3CR1+ effector-like exhausted cell (Texeff-like) differentiation. Overexpression of KLF2 converted CX3CR1⁻ cells into Texeff-like cells by direct engagement of key loci. Conversely, loss of KLF2 increased inhibitory receptor expression and redirected cells toward terminal exhaustion. However, early after infection, KLF2 deficiency yielded increased CD8+ T cell accumulation and improved viral control. This effect was, in part, mediated by TOX and improved T cell localization with dendritic cells. Additional deletion of PD-1 further enhanced viral control but induced severe immunopathology. Collectively, these findings identify KLF2 as a central regulator of the Texeff-like program and underscore exhaustion features as checkpoints balancing antiviral immunity and immunopathology.

Keywords:  CD8(+) T cell; CX3CR1; KLF2; PD-1; S1PR1; T cell exhaustion; TNF; anti-viral; chronic infection; effector-like cells; immunopathology; immunotherapy; in vivo pooled CRISPR screening

DOI:  https://doi.org/10.1016/j.immuni.2026.03.029
Science. 2026 Apr 30. 392(6797): eadq2080

Lymphoid tissue chemokines limit priming duration to preserve CD8+ T cell functionality.

Lukas M Altenburger, Daniela Claudino Carvoeiro, Philippe Dehio, Jianwen Zhou, Chiara Laura, Àlex Bofi I Cuadros, Mitali Katoch, Caroline Krüger, Juliana Barreto de Albuquerque, Petra Pfenninger, Jose Martínez Magdaleno, Matthias Mehling, Matteo Iannacone, Ali Hashemi Gheinani, Jörn Dengjel, Jun Abe, Jens V Stein.

The generation of effector CD8+ T cells (TEFF) requires activation of naïve CCR7+ T cells (TN) by dendritic cells (DCs) in lymphoid tissue. How TN-DC interaction duration and signal integration are controlled remains unclear. In this study, we show that lymphoid stroma-secreted CCR7 ligands limit interaction duration by progressively inducing CD8+ T cell release from DCs. At late interaction stages, CCR7 ligands relocalize the F-actin regulator DOCK2 away from the DC interface, permitting T cell detachment, proliferation onset, and acquisition of cytotoxicity. Disruption of CCR7 signaling causes prolonged T cell-DC contacts and produces dysfunctional TEFF with elevated inhibitory receptors, reduced antimicrobial activity, and impaired recall responses. Stromal chemokines therefore act as critical regulators of T cell priming by DCs, preserving CD8+ effector function during acute and memory phases.

DOI: https://doi.org/10.1126/science.adq2080
Int Immunopharmacol. 2026 Apr 28. pii: S1567-5769(26)00590-4. [Epub ahead of print]181 116744

PTK6 promotes ferroptosis resistance and CD8+ T cell exhaustion in pancreatic tumors via reprogramming glucose and lipid metabolism.

Rui Zheng, Si Wang, Dan Li, Xing Tian, Lifeng Sun, Jiao Wang, Yuchang Wang, Xuyi Pan, Yifan Liang, Zhihang Yang.

  Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor associated with poor prognosis and high mortality. The distinct metabolic reprogramming of nutrients in PDAC fosters an immunosuppressive tumor immune microenvironment (TIME) and compromises the efficacy of immunotherapy. Protein tyrosine kinase 6 (PTK6) is highly expressed in multiple solid tumors and contains a short N-terminal region featuring an SH2 domain capable of lipid binding, suggesting its involvement in lipid metabolic reprogramming within the malignant tumor microenvironment. Using PTK6-knockout mouse models and lipidomic sequencing, we investigated how PTK6 drives metabolic dysregulation and immune effector exhaustion in pancreatic tumors. Our findings uncover a "dual driver" role for PTK6 in PDAC progression: While it enhances cancer cell resistance to ferroptosis by the reprogramming lipid metabolism, it also promotes CD8+ T cell exhaustion through upregulating PD-1 and Tim-3 expression, ultimately driving immunosuppression. In summary, these findings identify PTK6 as a potential biomarker in PDAC and reveal a previously unrecognized role of PTK6 in linking tumor lipid metabolism to CD8+ T cell exhaustion. These data suggest that PTK6 may represent a candidate mechanistic target for further therapeutic exploration.

Keywords:  CD8(+) T cell exhaustion; Glucose and lipid metabolism; PTK6; Pancreatic tumor; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.intimp.2026.116744
Sci Immunol. 2026 May;11(119): eadz0348

Citraconate preserves T cell stemness and antitumor immunity.

Wenhui Li, Minmin Ge, Ziyi Luo, Minju Ni, Kexin Tang, Chenfeng Han, Jiajia Wang, Yifu Ma, Xiaowei Liu, Kaili Ma, Jingxing Yang, Wenjing Li, Cangang Zhang, Qitai Zhao, Guangcan Shao, Jaeoh Park, Yi Zhang, Yonghong Wan, Baojun Zhang, Gang Wang, Mingjing Shen, Qiang Shan, Feng Guo, Ping-Chih Ho, Liyuan Zhang, Lianjun Zhang.

Metabolic perturbations in the tumor microenvironment profoundly compromise the stemlike properties and effector functions of CD8 T cells. Deciphering the metabolic circuitry that sustains T cell stemness is critical for reinvigorating tumor-infiltrating lymphocytes and augmenting immunotherapeutic efficacy. Here, we identify citraconate, an itaconate isomer, as a metabolite markedly depleted in CD8 T cells subjected to chronic antigen stimulation or hypoxic conditions. Citraconate supplementation preserves stemlike characteristics, attenuates ferroptosis, and potentiates T cell-mediated antitumor immunity. Mechanistically, citraconate maintains intracellular cyclic adenosine monophosphate (cAMP) concentrations by suppressing phosphodiesterase1A/C (PDE1A/C) expression and preserving mitochondrial integrity, thereby activating protein kinase A (PKA) signaling. This activation transcriptionally represses arachidonate-5-lipoxygenase (ALOX5), consequently reducing arachidonic acid peroxidation. Clinically, diminished ALOX5 or PDE1A expression correlates with reduced T cell exhaustion and improved responses to immune checkpoint blockade (ICB) therapy. Our findings reveal the citraconate-mediated PDE1-cAMP-ALOX5 axis as a potential therapeutic target for enhancing cancer immunotherapy.

DOI: https://doi.org/10.1126/sciimmunol.adz0348
J Nanobiotechnology. 2026 Apr 28.

Extracellular vesicles inherit lactate from aggregated MSCs to alleviate type 1 diabetes mellitus via H2S-induced CD8+ T cell exhaustion.

Qianhui Ren, Qianmin Ou, Zhengshi Li, Luhan Niu, Deqian Tang, Xinyu Liu, Xueli Mao, Songtao Shi.

  Aggregated mesenchymal stromal cells (MSCs) show enhanced anaerobic glycolysis and elevated lactate production when compared to conventional adherent MSCs. It is unknown whether their extracellular vesicles (EVs) inherit lactate from parent cells and regulate anaerobic glycolysis in recipient cells. Here we show that aggregated MSC-derived EVs (agg-EVs) have superior therapeutic effects on type 1 diabetes mellitus (T1DM) with significantly reduced hyperglycemia, improved pancreatic islets, and elevated CD8+ T cell exhaustion. Mechanistically, we found that agg-EVs inherited lactate from aggregated MSCs to enhance L-cysteine decomposition in CD8+ T cells. Non-targeted metabolomics analysis revealed that agg-EV-treated CD8+ T cells showed elevated L-cysteine metabolism as well as reduced L-cysteine, glutathione (GSH) and GSH/GSSG (glutathione disulfide) ratio, resulting in an increased hydrogen sulfide (H2S) level. H2S can activate β-catenin to upregulate programmed cell death protein 1 (PD-1) expression and, therefore, suppress CD8+ T cell proliferation and function. Blockage of L-cysteine decomposition by knockdown pyruvate kinase M2 (PKM2) in aggregated MSCs or knockout of cystathionine γ-lyase to reduce H2S level in CD8+ cells diminished agg-EV-mediated therapeutic effects. These findings identify a previously unknown mechanism by which agg-EVs induce CD8+ T cell exhaustion via H2S/β-catenin/PD-1 axis in T1DM immunotherapy.

Keywords:  Aggregated mesenchymal stromal cells; CD8+ T cell exhaustion; Extracellular vesicles; Hydrogen sulfide; L-cysteine metabolism; Lactate

DOI:  https://doi.org/10.1186/s12951-026-04466-3
bioRxiv. 2026 Apr 13. pii: 2026.04.11.716570. [Epub ahead of print]

Serial vaccination expands and refines human CD4 + T cell memory.

Yi-Hui Lai, Xi Su, Silina Awad, Asgar Ansari, Juneil Jang, Ali O Saber, Huang-Wen Chen, Hannah Jung, Annesha Sarkar, Elizabeth M Drapeau, Warren B Bilker, Scott E Hensley, Laura F Su.

CD4 + T cells coordinate protective immunity against pathogens. However, a major unresolved question is how human CD4 + T cell memory is established and evolves following primary and repeated vaccination. Using COVID-19 mRNA vaccination as a model, we tracked 50 distinct antigen-specific populations directly ex vivo with peptide-MHC class II tetramers in eight SARS-CoV-2-naïve individuals from pre-vaccine baseline through memory time points after three mRNA doses. Our findings identify the primary vaccine series as the main driver of memory pool size. It leverages pre-existing memory while preferentially recruiting high-avidity T cells, establishing an immunodominance hierarchy dominated by a small subset of precursors. Booster vaccination refines both the magnitude and quality of T cell memory. It increases select populations and enhances differentiation of subdominant CD4 + T cells. Populations that did not become more abundant after boosting retained their polyfunctional potential. Beyond establishing memory to the ancestral spike, vaccinations broadened responses by recruiting cross-reactive T cells recognizing viral variants. Collectively, these findings reveal how human CD4 + T cell memory evolves through sequential immunizations to generate a functionally diverse and broadly responsive memory repertoire against future viral challenges.

DOI: https://doi.org/10.64898/2026.04.11.716570
Cell Commun Signal. 2026 Apr 29.

Metabolic reprogramming of Th17/Treg imbalance in autoimmune thyroid diseases.

Mengli Zhou, Weijie Wu, Yingzhao Liu, Shengjun Wang, Huiyong Peng.

  Autoimmune thyroid diseases (AITDs), including Hashimoto's thyroiditis and Graves' disease, arise from thyroid-specific autoimmunity driven by a breakdown of immune tolerance and dysregulated T-cell responses. Within this immune network, imbalance between T helper 17 (Th17) cells and regulatory T (Treg) cells has emerged as a major determinant of persistent inflammation and defective immune restraint. These two subsets are supported by distinct but interconnected metabolic programs. Th17 cells preferentially engage glycolytic and anabolic pathways to sustain inflammatory activity, whereas Treg cells rely more strongly on oxidative metabolism and mitochondrial fitness to preserve lineage stability and suppressive function. In AITDs, these intracellular programs are further reshaped by disease-associated microenvironmental cues, including excess iodine, oxidative stress, lactate accumulation, inflammatory cytokines, and tissue-derived stromal signals. This review summarizes how glucose, lipid, mitochondrial, and amino acid metabolism collectively regulate Th17 and Treg differentiation and function. We further examine how these pathways are altered in AITDs and distorted in thyroid and orbital tissues to amplify immune disequilibrium. Finally, we discuss emerging therapeutic strategies aimed at targeting immune metabolic circuits to restore immune homeostasis.

Keywords:  Autoimmune thyroid diseases; Immunometabolism; Metabolic reprogramming; Regulatory T cells; T helper 17 cells

DOI:  https://doi.org/10.1186/s12964-026-02915-y
Res Sq. 2026 Mar 13. pii: rs.3.rs-8941883. [Epub ahead of print]

Vaccination rescues dysfunctional T cell therapy by amplifying rare stem-like antitumor CD8⁺ T cells.

Sri Krishna, Zhiya Yu, Mohona Chakravarti, Victoria Dulemba, Aaron Dinerman, Lior Levy, Kyle Hitscherich, Jared Gartner, Sivasish Sindiri, Kristen Skonieczny, Todd Prickett, Paul Robbins, Stephanie Goff, Frank Lowery, James Yang, Steven Rosenberg.

Most antitumor CD8 ⁺ T cells in patients exhibit dysfunctional phenotypes, limiting the efficacy of adoptive cell transfer (ACT) against cancer. Although cancer vaccines can induce antitumor stem-like T cell (T SL ) phenotypes, whether they can reverse T cell dysfunction during ACT remains unclear. Using murine neoantigen-specific tumor models, we show that concurrent neoantigen-vaccination enhances the antitumor activity of ACT-products dominated by dysfunctional T cells, relying on host antigen-presenting cells. Vaccination remodels the immunosuppressive tumor microenvironment and promotes the expansion of T SL cells into tumors and lymphoid organs. Mechanistically, vaccination does not directly rescue dysfunctional T cells; but selectively amplifies low-frequency T SL (as low as 0.1% in infusion) to mediate tumor control. Analysis of human dysfunctional TIL-ACT infusion products containing scarce antitumor T SL cells (~1%) administered to a patient with metastatic melanoma corroborated these findings, demonstrating complete clinical tumor regression and expansion of adoptively transferred tumor-specific-TIL clonotypes only after vaccination. These data suggest that concurrent vaccines can unlock the therapeutic potential of rare stem-like T cells within otherwise ineffective dysfunctional ACT.

DOI: https://doi.org/10.21203/rs.3.rs-8941883/v1
J Biochem Mol Toxicol. 2026 May;40(5): e70854

Remodeling the Tumor Immune Microenvironment by Traditional Chinese Medicine: Mechanisms Focusing on TAM Polarization and CD8+ T Cell Exhaustion.

Yannan Geng, Yuanjun Qu, Ji Li, Xinfeng Wang, Changying Ji, Guangze Wang.

  This review focuses on two core immunosuppressive mechanisms within the tumor immune microenvironment (TIME): the polarization of tumor-associated macrophages (TAMs) towards an M2 phenotype and the functional exhaustion of CD8⁺ T cells. We systematically elucidate the multi-dimensional strategies by which Traditional Chinese Medicine (TCM) remodels the TIME. The article first dissects the interplay between TAMs and CD8⁺ T cells and their pivotal role in tumor immune escape. It then comprehensively reviews how TCM formulations and active components, through their characteristic multi-target actions, coordinately reverse TAM polarization and T cell exhaustion by modulating key signaling pathways (e.g., STAT, PI3K/Akt), reprogramming cellular metabolism (e.g., glycolysis, oxidative phosphorylation), and reshaping cytokine networks. Particular emphasis is placed on metabolic reprogramming as an upstream "bridging" mechanism that concurrently regulates both processes. Finally, the review explores the synergistic potential of combining TCM with immune checkpoint inhibitors and analyzes current challenges, including compositional complexity, insufficient mechanistic depth, and a paucity of high-quality clinical evidence. This work aims to provide a theoretical foundation and forward-looking perspective for developing novel TCM-based strategies in cancer immunotherapy.

Keywords:  CD8+ T‐lymphocytes; immunotherapy; traditional Chinese medicine; tumor immune microenvironment; tumor‐associated macrophages

DOI:  https://doi.org/10.1002/jbt.70854
Semin Immunol. 2026 Apr 27. pii: S1044-5323(26)00014-X. [Epub ahead of print]82 102027

Macronutrient availability and immune cell responses.

Paulo Estevão, Ana Júlia Estumano Martins, Pedro M Moraes-Vieira.

  Nutritional status and dietary composition profoundly influence immune responses, with carbohydrates, lipids, and proteins, acting as key regulators of immune cell metabolism, activation, and function. This review synthesizes current evidence on how these macronutrients shape the behavior of innate and adaptive immune cells, including monocytes, macrophages, dendritic cells, neutrophils, T cells, and B cells. We discuss how glucose and fructose differentially modulate inflammatory pathways, trained immunity, and antiviral responses; how saturated and polyunsaturated fatty acids affect immune cell signaling and cytokine production; and how amino acid availability influences metabolic reprogramming, polarization, and effector functions. Emerging findings highlight the complex, context-dependent roles of macronutrients in health and disease, revealing their potential as dietary targets in immune-mediated conditions. Understanding these interactions provides a foundation for nutritional strategies aimed at modulating immunity in metabolic, infectious, and inflammatory diseases.

Keywords:  Inflammation, immunometabolism, immune cells; Macrophages; Metabolism; Nutrient sensing, fatty acids; Nutrients

DOI:  https://doi.org/10.1016/j.smim.2026.102027
J Leukoc Biol. 2026 Apr 25. pii: qiag052. [Epub ahead of print]

T cell exhaustion: Next-generation target of autoimmune diseases?

Yuzhen Ouyang, Mengchuan Luo, Kailin Li, Kangzhi Chen, Zeyi Wen, Qian Zhou, Guanzhong Shi, Siyu Xu, Zhaohui Luo, Huan Yang.

  Exhausted T cells (Tex), characterized by impaired cytotoxic function, play a detrimental role in anti-tumor and anti-infection immunity but represent promising therapeutic targets for autoimmune diseases. Persistent exposure to auto-antigens drives autoreactive CD8+ or CD4+T cells toward an exhausted state, thereby mitigating excessive damage to healthy tissues. Inducing T cell exhaustion may offer a targeted approach to suppress pathological autoimmunity. In this review, we describe the markers, characteristics, and developmental phases of T cell exhaustion, discuss its close association with autoimmune diseases, and highlight Tex as a potential biomarker. We also summarize Tex-targeted therapeutic strategies, including inhibitory receptor activation, TCR overstimulation, and metabolic intervention, to provide insights for future treatments. The clinical translation gap of Tex-targeted therapy has also been proposed from stability, safety, and disease-specific considerations. Although challenges remain in areas such as antigen specificity and tenuous tolerance, therapies targeting Tex hold considerable potential to disrupt pathogenic circuits, realize disease remission, and reduce the risk of relapse in autoimmune diseases.

Keywords:  Autoimmune diseases; Autoreactive T cell; Inhibitory receptors; T cell exhaustion; Targeted immunotherapy

DOI:  https://doi.org/10.1093/jleuko/qiag052
Mucosal Immunol. 2026 Apr 27. pii: S1933-0219(26)00048-6. [Epub ahead of print]

CTL lymph node entrapment drives lymphopenia in severe influenza infection.

Aira F Cabug, Nichollas E Scott, Heran Zhang, Katherine Kedzierska, Linda M Wakim.

  Influenza virus infection can result in outcomes ranging from moderate, self-limiting illness to severe, life-threatening disease. Although severe cases are frequently associated with CD8+ T cell lymphopenia, the underlying mechanisms driving this diminished T cell response remain poorly defined. Here, we investigated how severe influenza infection alters CD8+ T cell activation and trafficking. While CD8+ T cell priming was comparable between moderate and severe influenza infections, we found that during severe disease, effector CD8+ T cells were retained within the lung-draining lymph nodes (dLN). This entrapment was, in part, associated with a failure of effector CD8+ T cells to re-express the transcription factor KLF2 and its downstream target, the sphingosine-1-phosphate receptor S1PR1, a defect we show to be independent of both TGFβ and sustained TCR signalling. To evaluate the consequences of this impaired trafficking, we transferred effector CD8+ T cells directly into the bloodstream during severe influenza infection and found that intravenously delivered cells were rapidly and selectively eliminated upon entry into the inflamed lung. Our findings reveal that CD8+ T cell lymphopenia observed during severe influenza infection arises from two key mechanisms: sequestration of effector CD8+ T cells within the dLN and selective elimination of antigen-specific effectors within the lung tissue.

Keywords:  CD8+ T cell trafficking; Influenza; Lymph node entrapment

DOI:  https://doi.org/10.1016/j.mucimm.2026.04.007
Aging Cell. 2026 May;25(5): e70527

T Cell Immunosenescence in Inflammatory Skin Diseases: Pathogenesis and Therapeutic Targets.

Conghui Liu, Ming Yang, Fugang Xiao, Jinrong Zeng.

  T cell immunosenescence refers to the progressive functional decline of T lymphocytes with aging, characterized by the phenotypic markers, mitochondrial dysfunction, and the senescence-associated secretory phenotype (SASP), representing a pivotal aspect of overall immune aging. This review systematically elucidates the critical role of T cell immunosenescence in the pathogenesis of common inflammatory skin diseases, including psoriasis, atopic dermatitis, rosacea, and seborrheic dermatitis. Senescent T cells drive the production of a disease-specific SASP via internally dysregulated signaling networks such as NF-κB, JAK-STAT, p38 MAPK, and PI3K-Akt-mTOR pathways, thereby shaping and sustaining a chronic cutaneous inflammatory microenvironment that promotes disease chronicity and recurrence. Furthermore, this review summarizes current therapeutic strategies targeting these senescence-associated pathways and SASP components, discussing both biological agents and small molecule inhibitors. Finally, we propose future research directions focusing on the direct targeting of senescent T cells or their upstream regulatory hubs to achieve deep disease remission and overcome therapeutic resistance.

Keywords:  SASP; T cell immunosenescence; inflammatory skin diseases; signal transduction; targeted therapy

DOI:  https://doi.org/10.1111/acel.70527
J Immunol. 2026 Apr 15. pii: vkag073. [Epub ahead of print]215(4):

Lactate conditioning reprograms mucosal-associated invariant T cell metabolism boosting effector function.

Ardena Berisha, Benjamin J Jenkins, Nidhi Kedia-Mehta, Eimear K Ryan, Shauna Mayock, Odhran Ryan, Cian Davis, Helen Heneghan, Donal O'Shea, Nicholas Jones, Andrew E Hogan.

  Mucosal-associated invariant T (MAIT) cells are unconventional T cells, which upon activation can display potent cytotoxic and cytokine-producing capabilities. Together, these features make MAIT cells promising candidates for cancer immunotherapy. In this study, we show that MAIT cells can be efficiently amplified in vitro, and these amplified MAIT cells are armed with potent anticancer functions, including the ability to produce significant amounts of effector molecules such as IFNγ and granzyme B. Excitingly, we demonstrate that MAIT cells can be redirected to potently kill cancerous cells using a clinically relevant bispecific monoclonal antibody. Furthermore, in an attempt to metabolically condition MAIT cells to improve function, we demonstrate that MAIT cells possess the molecular machinery to transport and metabolize lactate, an abundant metabolite within the solid tumor microenvironment. Activating MAIT cells in the presence of exogenous sodium lactate remodels their cellular metabolism, with a significant increase in mitochondrial metabolism. Functionally, this supports elevated production of effector molecules (IFNγ, granzymes A and B), leading to boosted engager mediated MAIT cell cytotoxicity. These data collectively show that MAIT cells can be pharmacologically directed to target cancer cells and in vitro conditioning using sodium lactate can enhance their anticancer capabilities through reprogrammed cellular metabolism. Our findings represent a novel strategy for a potential new adoptive cancer immunotherapy.

Keywords:  BiTEs; immunotherapy; lactate; mucosal associated invariant T cells

DOI:  https://doi.org/10.1093/jimmun/vkag073
iScience. 2026 May 15. 29(5): 115642

Newly isolated human-derived Lactobacillus fermentum strain stimulates IFN-γ-secreting CD8+ T cells for enhanced anti-cancer immunity.

Tae-Young Kim, Seungil Kim, Sohyeon Lee, Su-Hyun Lee, Jiyoung Yu, Kyunggon Kim, Mi-Na Kweon.

  The gut microbiota represents a promising target to enhance cancer immunotherapy, yet the microbial molecules mediating anti-tumor immunity remain poorly defined. Here, we identify a human-derived strain, Lactobacillus fermentum MI37, that augments anti-tumor immune responses and synergizes with anti-PD-1 therapy. MI37 induces robust IFN-γ production with minimal IL-10, increases tumor-infiltrating cytotoxic T lymphocytes, and upregulates inflammatory gene programs in a syngeneic mouse model. Notably, heat-killed MI37 retains its immunostimulatory and anti-tumor effects, indicating a structural microbial component mediates activity. Fractionation identifies lipoteichoic acid (LTA) as the key effector and purified Staphylococcus aureus-derived LTA recapitulates MI37-induced IFN-γ production and CD8+ T cell activation. Genomic and proteomic analyses further reveal MI37-specific features in teichoic acid biosynthesis, including a distinctive sulfatase N-terminal domain-containing LTA synthase. These findings establish LTA-producing probiotics as potential microbial adjuvants to improve cancer immunotherapy efficacy.

Keywords:  Cancer; Immunology; Microbiology

DOI:  https://doi.org/10.1016/j.isci.2026.115642
J Exp Med. 2026 Jun 01. pii: e20250194. [Epub ahead of print]223(6):

Tet2 deficiency alters CD4+ T cell function and promotes T cell lymphoma with a TFH cell immunophenotype.

Tayla B Heavican-Foral, Yuping Li, Waseem Lone, Alyssa Bouska, Jibin Zhang, Ruimeng Yang, Xuxiang Liu, Ab Rauf Shah, Abdul Rouf Mir, Joseph Rohr, Dylan Jochum, Anurag Kumar, Ravneet Singh Chawla, Catalina Amador, Jiayu Yu, Tyler Herek, Jacob Robinson, Chengfeng Bi, Sunandini Sharma, Tyler Gilbreath, R Katherine Hyde, Timothy W McKeithan, Chan-Wang Lio, Anjana Rao, Giorgio Inghirami, Joesph Khoury, Wing C Chan, Javeed Iqbal.

TET2 mutations are frequent in TFH-derived lymphomas, but how epigenetic disruption initiates malignant T cell transformation is unclear. We generated Cd4cre;Tet2FL/FL mice, which developed aggressive T cell lymphoma (m-TCL) with a TFH cell-like immunophenotype. Genome-wide transcriptomics and epigenetic profiling of Tet2-/- CD4+ T cells prior to lymphoma development showed hyperactive TCR, PI3K signaling, and dysregulated TH differentiation program, with proliferation promoting signal transduction at the lymphoma stage. Tet2 loss promoted hyperplasticity under in vitro conditions but favored conditional TFH differentiation. Reduced 5-hmC levels at regulatory genomic elements, resulted in transcriptional rewiring of TFH-associated genes, promoting ICOS(L)-mediated PI3K signaling. TET2-KO human CD4+ T cells showed conserved epigenetic changes with increased proliferation, decreased exhaustion, increased memory marker expression, and clonal expansion with restricted TCR repertoire under in vitro conditions. scRNA-seq revealed a persistent proliferative cluster characterized by elevated stem-like transcriptional features compared with WT counterparts. Tet2-/- m-TCLs allografted into NSG mice showed a significant response to epigenetic (5-azacytidine) and PI3K inhibitors (duvelisib) alone or in combination.

DOI: https://doi.org/10.1084/jem.20250194
Aging Dis. 2026 Apr 29.

Peanut Procyanidin A Delays Hematopoietic Stem Cells Aging through Cox5a.

Ying Wang, Bingzheng Zhang, Junfei Lu, Lin Liu, Xiaoyu Tang, Changzheng Li, Xi Zeng, Chuqing Fan, Yuncong Qiao, Cheng Chen, Yu Zhang, Jiajia Chen, Zhiyi Li, Yucheng Luo, Guizhi Yang, Juan Shen, Bing Liu.

Hematopoietic stem cells (HSCs) are essential for maintaining blood system homeostasis. Their aging leads to functional decline and increased susceptibility to blood disorders, largely driven by elevated reactive oxygen species (ROS). Here, we identify peanut procyanidin A (PPA) as a potent compound that delays HSC aging by targeting cytochrome c oxidase subunit 5a (Cox5a). Through screening of 234 FDA-approved natural compounds, we found that PPA significantly reduces mitochondrial ROS and improves the function of aged HSCs in mice. Transcriptomic analysis revealed that PPA induces a metabolic shift from oxidative phosphorylation toward glycolysis, reminiscent of a youthful HSC state. Moreover, PPA rescues aging phenotypes in human CD34+ hematopoietic progenitor cells. Our study establishes Cox5a as a druggable target for HSC rejuvenation and highlights PPA as a promising therapeutic candidate for age-related hematopoietic decline.

DOI: https://doi.org/10.14336/AD.2025.1354
bioRxiv. 2026 Apr 17. pii: 2026.04.14.718497. [Epub ahead of print]

Gut-derived metabolic reprogramming drives immune aging and tissue degeneration.

Sayan Ghosh, Victoria Koontz, Ying Xin, Sridhar Bammidi, Dominique Meyer, Haochen Wang, Vishnu Suresh Babu, Puja Dutta, Durgadas Cherukaraveedu, Shreevadsaa A Mohanakrishnan, Anupam K Mondal, Jagannath Das, Jenny Nguyen, Avinash Soundararajan, Idris A Adekale, Dulal Bhaumik, Stacey Hose, Sheldon Rowan, Padmanabhan P Pattabiraman, Rangaramanujam M Kannan, James T Handa, Ji Yi, Srinivasa R Sripathi, Jiang Qian, Debasish Sinha.

Aging is characterized by changes in gut microbiome, metabolic imbalance and chronic inflammation, yet how these processes integrate to drive tissue degeneration remains poorly defined. Using age-related macular degeneration (AMD) as a model of tissue aging, we identify a diet-induced metabolic-immune axis that promotes systemic and retinal degeneration. In mice, a high-fat, cholesterol-enriched (HFC) diet induced perturbations in the gut structural integrity and microbiome repertoire, as well as systemic metabolic aging signatures, prominently marked by reduced circulating histidine. Plasma histidine levels were similarly decreased in AMD patients and inversely correlated with body mass index (BMI) in control donors. These diet-induced gut microbiome changes and subsequent metabolic alterations promoted peripheral innate immune reprogramming, with expansion of inflammatory neutrophils and monocytes that infiltrated the outer retina in a mouse model. Mechanistically, the gut-derived IGF1R/AKT2 signaling acts as a central regulator of global epigenetic remodeling and systemic immune aging under high-fat conditions in C. elegans . In a mouse model with an age-dependent dry AMD-like pathology, distinct retinal pigment epithelium (RPE) subpopulations exhibited downregulation of the histidine transporter SLC7A5, linking metabolic stress to activation of MIF/CD74-dependent inflammatory signaling between RPE and infiltrating immune cells. Histidine supplementation or AKT2 phospho-state modulation attenuated systemic immune activation and rescued retinal degeneration. These findings identify histidine-axis dysregulation as a mechanistic bridge between diet-induced microbiome changes, metabolic stress, immune aging, and retinal degeneration.

DOI: https://doi.org/10.64898/2026.04.14.718497
bioRxiv. 2026 Apr 14. pii: 2026.04.12.717050. [Epub ahead of print]

Canonical WNT Ligands Produced by Regulatory T Cells Restrain Effector CD4 + T Cell Responses.

Kashish Singh Parihar, Margaret R Niemeier, Igal Ifergan.

Regulatory T cells (Tregs) are essential for maintaining immune homeostasis by suppressing excessive activation of effector T cells. Although several mechanisms of Treg-mediated suppression have been described, the molecular signals that contribute to this regulation remain incompletely understood. WNT signaling, best known for its roles in development and tissue homeostasis, has recently emerged as an important regulator of immune function, but its contribution to Treg-mediated immune suppression is largely unknown. Here, we show that Tregs preferentially express multiple canonical WNT ligands, including WNT2B, WNT3, WNT7B, and WNT10B, compared with conventional CD4 + T cells. These WNT proteins were detected intracellularly in Tregs, and WNT2B and WNT3 were actively secreted into culture supernatants. Conventional CD4 + T cells expressed Frizzled receptors capable of sensing these ligands. Pharmacological inhibition of canonical WNT signaling using the antagonist mDKK-1 enhanced CD4 + T cell activation and proliferation and increased pro-inflammatory cytokine expression, while anti-inflammatory IL-10 remained unchanged. Together, these findings identify Tregs as a source of canonical WNT ligands and suggest that Treg-derived WNT signaling contributes to the suppression of effector CD4 + T cell responses. This work reveals a previously underappreciated pathway through which Tregs regulate immune activity and identifies WNT signaling as a potential target for modulating inflammatory immune responses.

DOI: https://doi.org/10.64898/2026.04.12.717050
J Immunol. 2026 Apr 15. pii: vkag089. [Epub ahead of print]215(4):

Deficiency of microRNA-10a in CD4+ T cells protects against intestinal infection through mitochondrial oxidation-IL-22 pathway.

Wenjing Yang, Tianming Yu, Suxia Yao, Yingzi Cong.

  Interleukin 22 (IL-22) produced by CD4+ T cells plays an important role in regulating intestinal immune responses during inflammation and infection, but the mechanisms controlling IL-22 expression in T cells remain incompletely understood. MicroRNA-10a (miR-10a) is known to regulate CD4+ T-cell function, but its role in IL-22 production has not been defined. Here, using mouse CD4+ T cell-specific miR-10a knockout models, we examined how miR-10a regulates IL-22 expression and the underlying metabolic mechanisms. MiR-10a deficiency led to increased IL-22 production in CD4+ T cells both in vitro and in vivo, under steady and inflammatory conditions. CD4+ T cell-specific miR-10a knockout mice were resistant to Citrobacter rodentium infection, and the protection was abolished when blocking the IL-22 pathway in mice. Mechanistically, miR-10a-deficient CD4+ T cells exhibited increased mitochondrial oxidative metabolism and membrane potential. Pharmacologic inhibition of mitochondrial complex III with antimycin A suppressed the enhanced IL-22 production in miR-10a-deficient T cells. We further identified Uqcrq, a subunit of mitochondrial complex III, as a direct target of miR-10a, and loss of Uqcrq suppressed IL-22 production in CD4+ T cells. Together, these findings identify miR-10a as a T cell-intrinsic regulator of mitochondrial oxidative metabolism that constrains IL-22 production in the intestine.

Keywords:   Uqcrq ; IL-22; microRNA-10a; mitochondrial oxidation

DOI:  https://doi.org/10.1093/jimmun/vkag089
Proc Natl Acad Sci U S A. 2026 May 05. 123(18): e2527753123

Cytochrome P450 1B1 directs pathogenic Th17 cell generation and autoimmune disease by fine-tuning redox homeostasis and mitochondrial integrity.

Wenhao Hu, Yunqing Sun, Jie Sun, Yue Liang, Suoqin Jin, Jing Liu, Bing Wu.

  Th17 cell function is highly context-dependent and can be categorized into pathogenic and nonpathogenic Th17 cell subsets. Understanding the molecule control of pathogenic Th17 (pTh17) cell immunity will benefit the treatment for related autoimmune diseases. Here, we revealed that cytochrome P450 1B1 (CYP1B1) is highly upregulated during mice and human colitis. CYP1B1 promoted both colon inflammatory diseases and colitis-associated colorectal cancer via pTh17-dependent but microbiota-independent manner. Notably, CYP1B1 specifically dictated the differentiation and pathogenicity of pTh17 cells, while having no effects on nonpathogenic Th17 cell generation. Mechanistically, CYP1B1 deficiency disrupted intracellular redox homeostasis via decreased glutathione synthetase, leading to increased ROS and mitochondrial dysfunction of pTh17 cells. ROS elimination by N-acetylcysteine or ectopic glutathione synthetase expression restored mitochondrial fitness and promoted pTh17 cell survival and generation. Taken together, our findings uncover a T cell intrinsic CYP1B1-ROS-mitochondrial axis in driving pTh17 cell generation, interfering with this hub may be beneficial for pTh17 cell-related immunopathology.

Keywords:  CYP1B1; ROS; colitis; mitochondrial; pathogenic Th17

DOI:  https://doi.org/10.1073/pnas.2527753123
Cancer Immunol Res. 2026 Apr 27.

An ICAM1-targeting chimeric costimulatory receptor mimics the immune synapse and enhances tumor-specific T cell function.

Irene M Min, Yanping Yang, Dessislava Stefanova, Yogindra Vedvyas, Diella S Babu, Dong-Hyun Lee, Yago Alcaina, Maria Cristina Riascos, Janusz Puc, Kevin J Chen, Juan Gonzalez-Valdivieso, Jose Thaiparambil, Maneeza Bilal, Bing He, Aidan C Burnett, Rasa Zarnegar, Thomas J Fahey, Moonsoo M Jin.

Engineered T cell therapies, such as chimeric antigen receptor (CAR) and T cell receptor (TCR)-based approaches, have transformed outcomes in hematological malignancies, yet their efficacy in solid tumors remains limited by tumor antigen escape, immunosuppressive microenvironments, and insufficient activation of CAR or TCR signaling. To overcome these barriers, we developed an intercellular adhesion molecule 1 (ICAM1)-specific chimeric costimulatory receptor (ICCR) engineered for expression in T cells to augment their activation. ICAM1 is broadly expressed across solid tumors and is further upregulated by IFNγ released during early T cell engagement, creating a feed-forward loop that reinforces tumor recognition. ICCR engagement with ICAM1 triggered NFκB signaling independently of TCR-p/MHC engagement; however, full T cell activation and cytotoxic function remained dependent on intact TCR signaling. In primary T cells, ICCR increased proliferation, cytokine production, and cytotoxicity, resulting in improved tumor control in two anaplastic thyroid cancer xenograft models treated with allogeneic or autologous ICCR-T cells. Mechanistically, ICCR strengthened tumor cell engagement, promoted selection and expansion of tumor-specific TCR clonotypes, and amplified downstream signaling pathways. These findings identify ICCR as a strategy that leverages an immune synapse-mimetic mechanism to enhance the function of low-activity tumor-specific TCRs and improve T cell responses in solid tumor microenvironments.

DOI: https://doi.org/10.1158/2326-6066.CIR-25-0529
JCI Insight. 2026 Apr 30. pii: e198701. [Epub ahead of print]

PD-1-targeted IL-15 mutein activates CD8+ and CD4+ T cells in infection and cancer.

Isaraphorn Pratumchai, Marie Bernardo, Julien Tessier, Jaroslav Zak, Kristi L Marquardt, Joon Sang Lee, Maheeka Bimal, AHyun Choi, Anthony M Byers, Mikielia G Devonish, Roberto Carrio, Dan Lu, Stella A Martomo, Jeegar Patel, Yu-An Zhang, Ingeborg M Langohr, Virna Cortez-Retamozo, Dinesh S Bangari, Angela Hadjipanayis, Xiangming Li, Valeria R Fantin, Donald R Shaffer, John R Teijaro.

  Immune checkpoint inhibitors have transformed cancer therapy, yet many patients fail to achieve durable responses due to insufficient T cell reinvigoration. Cytokines offer promise for enhancing immunotherapy, but their clinical use is limited by toxicity and a narrow therapeutic index. Immunocytokines, engineered fusion proteins combining antibody specificity with cytokine activity, aim to overcome these challenges by targeting cytokine delivery to immune cells or the tumor microenvironment. We describe SAR445877 (SAR'877), a novel PD-1-targeted immunocytokine that fuses a high-affinity anti-PD-1 antibody with a detuned IL-15/IL-15Rα sushi domain complex. SAR'877 blocks PD-1/PD-L1 and PD-1/PD-L2 interactions while selectively delivering IL-15 signals to PD-1+ T cells, enhancing proliferation and activation of antigen-experienced CD8+ and CD4+ T cells and NK cells, while minimizing systemic inflammation. Mechanistically, SAR'877 activates STAT5 signaling in PD-1+ lymphocytes and restores effector function in exhausted T cells. In preclinical models, a murine surrogate of SAR'877 accelerated viral clearance and induced robust anti-tumor immunity by expanding cytotoxic CD8+ T cells and promoting Th1 polarization. Notably, SAR'877 outperformed anti-PD-1 plus untargeted IL-15, highlighting the therapeutic potential of targeted IL-15 delivery. These findings position SAR'877 as a promising next-generation immunotherapy with enhanced efficacy and reduced cytokine-associated toxicities.

Keywords:  Cancer immunotherapy; Cytokines; Immunology; Immunotherapy; Oncology

DOI:  https://doi.org/10.1172/jci.insight.198701
Immun Ageing. 2026 Apr 29.

Inflammaging and the role of micronutrients as immunomodulators: a pathway to healthy aging.

Sheryl S L Tan, Vandana Garg, Abhijeet Dhiman, Nitu Bansal, Patricia Conway.

   BACKGROUND: Healthy aging is increasingly challenged by inflammaging, a chronic, low‑grade inflammatory state primarily exacerbated by gut microbiota dysbiosis and declining immune function. Persistent digestive and systemic inflammation, along with immunosenescence, contributes to multiple age‑related diseases. Micronutrients regulate key components of immune system and support the composition and function of the gut microbiota, underscoring their emerging role as modulators of inflammaging.
MAIN BODY: This narrative review synthesizes current evidence insights on how micronutrients regulate cellular and molecular drivers of inflammaging, with emphasis on immune function and gut microbiota imbalance. Adequate intakes of vitamins A, B‑complex, C, D, E, and K, together with trace elements (zinc, selenium, magnesium, iron, and copper), supports both innate and adaptive immune response, genomic and epigenetic stability, mitochondrial efficiency, telomere integrity, and immune regulation. Importantly, micronutrients influence gut microbial composition and inflammatory signaling pathways, thereby mitigating dysbiosis-driven digestive inflammation, a major contributor to systemic inflammaging. The review also delineates the bidirectional micronutrient-microbiome relationship, whereby microbial composition shapes nutrient bioavailability, while micronutrients influence microbial diversity, short‑chain fatty acid production, and inflammatory signaling.
CONCLUSION: Micronutrient sufficiency may help reduce digestive inflammation, restore microbial balance, and modulate immune pathways implicated in inflammaging. However, translating these benefits requires robust assessment of micronutrient status and gut microbiota. Developing standardized evaluation and microbiota‑informed nutrition strategies may enable more precise targeted interventions to support healthy aging.

Keywords:  Digestive inflammation; Gut microbiota; Healthy aging; Inflammaging; Leaky gut; Micronutrients

DOI:  https://doi.org/10.1186/s12979-026-00569-5
Front Nutr. 2026 ;13 1807302

The immunoregulatory effect of short-chain fatty acids in type 2 diabetes mellitus.

Jiaxin Li, Zhongmin Lv, Qi Fan, Peinan Fu, Ning Zhou, Jiefang Deng, Huimin Qi, Meng Yang.

  Short-chain fatty acids (SCFAs) are the primary metabolites of dietary fiber fermented by intestinal flora. They play a systemic role in the immune regulation of type 2 diabetes mellitus (T2DM) by integrating receptor-mediated signaling and epigenetic regulatory mechanisms. At the receptor pathway level, SCFAs activate G protein-coupled receptors such as GPR41/43/109 A, initiate downstream signaling cascades including MAPK, NF-κB, and mTOR/STAT3, and thereby achieve rapid modulation of immune cell function; at the epigenetic regulatory level, SCFAs induce chromatin remodeling and gene expression reprogramming by inhibiting histone deacetylase (HDAC) activity, giving immune cells long-term functional memory. These two pathways act coordinately to broadly regulate the functional status of innate and adaptive immune cells. In innate immune cells, SCFAs influence macrophage polarization, neutrophil activation, dendritic cell antigen presentation, mast cell degranulation, and eosinophil-mediated immune homeostasis; in adaptive immune cells, SCFAs regulate the differentiation of CD4 + T cell subsets, CD8 + T cell effector function, regulatory T cell stability, B cell antibody production and cytokine secretion of congenital lymphocytes (ILCs). These immunomodulatory effects are integrated in multiple metabolic organs such as adipose tissue, liver, islet and intestine to collectively improve T2DM-related chronic inflammation and insulin resistance. Investigation of SCFAs reveals the molecular basis of the interaction between intestinal flora and host immune metabolism, and provides a theoretical foundation for the prevention and treatment of T2DM based on dietary intervention or microecological regulation.

Keywords:  GPCR; HDAC; SCFAs; T2DM; adaptive immunity; innate immunity

DOI:  https://doi.org/10.3389/fnut.2026.1807302
bioRxiv. 2026 Apr 19. pii: 2026.04.15.718702. [Epub ahead of print]

Not so cold after all: tumor infiltrating CD8+ T cells in EBV-positive Burkitt lymphoma are quiescent, not exhausted.

Catherine S Forconi, Cliff I Oduor, Priya L Saikumar, Zachary J Racenet, Gavin Fujimori, Viriato M'Bana, Angela Matta, Jeni Melo, Fabienne Laderach, Titus K Maina, Juliana A Otieno, Dan Chepsidor, Kibet Kibor, Festus Njuguna, Terry Vik, Ann W Kinyua, Christian Munz, Jeffrey A Bailey, Ann M Moormann.

Survival outcomes for pediatric Burkitt lymphoma (BL) substantially vary depending on geography (50-90%), which also serves as a proxy for the prevalence of Epstein-Barr virus (EBV) within the tumors. Although BL is considered an immunologically "cold" tumor with few tumor-infiltrating lymphocytes (TILs), their functional status has not been fully evaluated, especially for EBV-positive disease. Here, we characterize the exhaustion and activation profiles of T cells in the tumor microenvironment (TME) of EBV-positive BL using orthogonal methods, single-cell gene expression analysis, spectral flow cytometry, and immuno-histochemistry staining (IHC). We found that CD8+ TILs displayed a mosaic of immune inhibitory gene expression encoding, PD1, TIGIT, LAG3 and HAVCR2/TIM3. IHC validated the expression of PD1 and TIGIT on CD8+ TILs, as well as their respective ligands, PDL-1, PVR, and Nectin-2 on malignant B cells. Despite exhaustion-associated signatures, CD8+ TILs retain cytotoxic potential, expressing granules (i.e. Granzyme A, Perforin) and cytokines (i.e. IFNγ) and demonstrate an increased uptake of metabolites such as glucose, arginine, and methionine. In peripheral blood, pediatric BL patients exhibited a significantly higher abundance of PD1+TIGIT+ CD8+ T cells compared to healthy children. Notably, these circulating T cells from BL patients express significantly lower levels of TOX, suggesting they are not irreversibly dysfunctional. Together, our results indicate that CD8+ T cells both in the TME and in circulation of children with BL are not terminally exhausted but remain poised for functional re-invigoration. These findings support the potential integration of immune checkpoint inhibitors into combination chemotherapeutic regimens to improve outcomes for these children.

DOI: https://doi.org/10.64898/2026.04.15.718702
Cell. 2026 Apr 29. pii: S0092-8674(26)00226-6. [Epub ahead of print]

Proteostasis sustains T cell differentiation potential and tumor-infiltrating lymphocyte function.

Nicole E Scharping, Xuezhen Ge, Maria Inês Matias, Fulin Jiang, Allison Cafferata, Maximilian Heeg, Alexander Monell, Giovanni Galletti, Kitty P Cheung, Angelica Rock, Nick Thao, Sydnye L Shuttleworth, Michael A Bauer, Kennidy K Takehara, Amir Ferry, Sara Quon, Brian Koss, Samuel A Myers, Eric J Bennett, Ananda W Goldrath.

  Tumor-infiltrating lymphocytes (TIL) often fail to restrain tumor growth due to progressive differentiation into an "exhausted" state. Tissue-resident memory T cells (TRM) maintain protection from infection for years in healthy tissues, and patient tumors that contain TIL with TRM features are associated with better prognosis. Proteomic and transcriptomic profiling of T cell populations identified proteostasis as a significant factor distinguishing TRM and progenitor-exhausted TIL from terminally exhausted TIL, including loss of E3 ubiquitin ligases NEURL3, RNF149, and WSB1, with accumulation of unfolded proteins despite functional proteasome activity. Enforced expression of these ligases in T cells preserved stem-like TCF1+ populations and improved function in tumors and chronic infection, whereas deficiency impaired TIL and altered T cell differentiation during acute infection. Sustained ligase expression rescued the accumulation of unfolded proteins in TIL and improved immunotherapy outcomes in preclinical models, underscoring the critical role of proteostasis in TIL function and highlighting a promising avenue for advancing cancer immunotherapy.

Keywords:  CD8(+) T cell; E3 ubiquitin ligase; T cell exhaustion; cancer; immunotherapy; proteostasis; tumor; tumor-infiltrating lymphocyte

DOI:  https://doi.org/10.1016/j.cell.2026.02.019
bioRxiv. 2026 Apr 19. pii: 2026.04.15.718788. [Epub ahead of print]

A microbiota-derived bile acid overcomes antibiotic-induced hyporesponsiveness to immune checkpoint therapy by enhancing CD8 + T cell antitumor immunity.

Wenling Li, Christina M Zarek, Hesuiyuan Wang, Shuheng Gan, Parastoo Sabaiefard, Priscilla Del Valle, Jiwoong Kim, Nicole Poulides, Laura A Coughlin, Jake N Lichterman, Cheng Zhang, Rebecca Suet-Yan Chiu, Tarun Srinivasan, Mauricio J Velasquez, Indu Raman, Vanessa J Maddox, Jeffrey McDonald, Ralf Kittler, Prithvi Raj, Xin V Li, Xiaowei Zhan, Chen Liao, Joao B Xavier, Andrew Y Koh.

Gut microbiota are critical determinants of effective immune checkpoint therapy (ICT), yet the microbial mediators and host mechanisms that enhance antitumor immunity remain poorly understood. Here, we identify the microbiota-derived bile acid taurodeoxycholic acid (TDCA) as a metabolite associated with immune checkpoint therapy (ICT) response. TDCA administration alone is sufficient to overcome antibiotic-induced ICT hyporesponsiveness across multiple murine tumor models. Mechanistically, TDCA directly enhances CD8⁺ T cell-mediated antitumor immunity, increasing cytotoxicity. These effects required signaling through the bile acid receptor TGR5. Together, these findings reveal TDCA as a gut microbial metabolite that restores ICT efficacy after antibiotic disruption by directly augmenting CD8⁺ T cell anti-tumor activity. This work supports metabolite replacement as a therapeutic strategy to mitigate antibiotic-associated loss of cancer immunotherapy response.
Significance: TDCA is a microbiota-derived metabolite that restores immune checkpoint therapy efficacy after antibiotic disruption by directly enhancing CD8⁺ T-cell-mediated anti-tumor immunity through bile acid receptor TGR5 signaling. Our findings suggest that supplementation with defined microbial metabolites can mitigate antibiotic-associated loss of immunotherapy response without requiring broader microbiome reconstitution.

DOI: https://doi.org/10.64898/2026.04.15.718788
Cell. 2026 Apr 30. pii: S0092-8674(26)00383-1. [Epub ahead of print]

Distinct in vivo dynamics of donor-derived stem cell memory CAR T cells post-allogeneic HSCT relapse.

Luca Gattinoni, Gabriele Inchingolo, Dennis C Harrer, Alberto Susana, Simone Puccio, Dragana Slavkovic-Lukic, Danielle A Natrakul, Nicholas Strieder, Christoph Heuser-Loy, Jeremy G Baldwin, Jessica Fioravanti, Yun Ji, Sanjivan Gautam, Chiara Suriano, Azucena Martín-Santos, Roland C Schelker, Nisha Patel, Jennifer Mann, Stephanie Goff, Lekha Mikkilineni, James C Yang, Mei Li M Kwong, Rashmika Patel, Michael Rehli, Steven L Highfill, David F Stroncek, Steven A Rosenberg, Luca Biasco, Enrico Lugli, Jennifer N Brudno, James N Kochenderfer.

  Donor-derived CD19-CAR T cells offer a therapeutic option for B cell malignancies relapsing after allogeneic hematopoietic stem cell transplantation but are often constrained by poor engraftment, expansion, and persistence. In a first-in-human study (NCT01087294), we found that CAR-modified stem-cell memory T (TSCM) cells exhibited greater expansion and persistence than standard CAR T cells, enabling complete responses at low doses in the absence of lymphodepletion. CAR TSCM cells induced mild cytokine-release syndrome, dominated by IFN-γ. Both products differentiated into effectors; however, only CAR TSCM cells robustly reconstituted the stem-like compartment over time. CAR TSCM cells were sustained through clonal succession, whereas persisting standard CAR T cells resulted from maintenance or contraction of early-expanded clones. While poor expansion limited standard CAR T cell activity, resistance to CAR TSCM cells was driven primarily by tumor- and host-related factors. These findings establish CAR TSCM cells as a promising platform for next-generation CAR T cell therapies.

Keywords:  B cell malignancies; CAR T cells; Phase 1 study; donor-derived T cells; stem cell memory T cells

DOI:  https://doi.org/10.1016/j.cell.2026.03.047
Nat Metab. 2026 Apr 29.

Nitrogen metabolism profiling reveals cell state-specific pyrimidine synthesis pathway choice.

Milan R Savani, Bingbing Li, Bailey C Smith, Wen Gu, Yi Xiao, Gerard Baquer, Tracey Shipman, Skyler S Oken, Namya Manoj, Lauren G Zacharias, Vinesh T Puliyappadamba, Sylwia A Stopka, Michael S Regan, Michael M Levitt, Charles K Edgar, William H Hicks, Soummitra Anand, Misty S Martin-Sandoval, Rainah Winston, João S Patrício, Xandria Johnson, Trevor S Tippetts, Diana D Shi, Andrew Lemoff, Timothy E Richardson, Pascal O Zinn, Ashley Solmonson, Thomas P Mathews, Nathalie Y R Agar, Ralph J DeBerardinis, Kalil G Abdullah, Samuel K McBrayer.

Stable isotope-tracing assays track few metabolites, yet cells use many nutrients to sustain nitrogen metabolism. Here we create a platform for tracing 30 nitrogen isotope-labelled metabolites in parallel to enable a system-level understanding of cellular nitrogen metabolism. This platform reveals that while primitive cells engage both de novo and salvage pyrimidine synthesis pathways, differentiated cells nearly exclusively salvage uridine. This link between cell state and pyrimidine synthesis pathway preference persists in murine and human tissues. Mechanistically, we find that S1900 phosphorylation of CAD, the first enzyme of the de novo pathway, is induced by uridine deprivation in differentiated cells and constitutively enriched in primitive cells. Mimicking CAD S1900 phosphorylation in differentiated cells constitutively activates de novo pyrimidine synthesis, while blocking this modification impairs the cellular response to uridine starvation. Collectively, we establish a method for nitrogen metabolism profiling and define a mechanism of cell state-specific pyrimidine synthesis pathway choice.

DOI: https://doi.org/10.1038/s42255-026-01520-0
Sci Rep. 2026 Apr 30.

Mathematical modeling of immune counter-regulation predicts efficacy of fractionated CD8+ T cell dosing strategies.

Hiroki Kasai, Koji Nagaoka, Artem Lysenko, Kazuhiro Kakimi, Tatsuhiko Tsunoda.

  Adoptive cell therapy (ACT) with tumor-specific CD8+ T cells (TSTs) induces tumor regression but rarely achieves durable responses in solid tumors. This limitation stems from secondary counter-regulatory mechanisms that are also induced by ACT, notably the recruitment of tumor-infiltrating myeloid cells (TIMs). However, the precise dynamics of these responses and the optimal TST dosing strategies to overcome their immunosuppression remain largely unclear. Here, we developed a mathematical model of ACT incorporating TIM-driven counter-regulation and simulated alternative TST dosing strategies based on data from B16F10 melanoma-bearing mice. Our models revealed that, compared with a single administration strategy, fractionated and response-guided dosing strategies reduced tumor burden by up to 83% while using about 40% fewer TSTs. These results were supported by transcriptomic analysis showing that ACT-induced TIMs initially exhibited pro-inflammatory traits but later shifted into suppressive states, suggesting that fractionated TST dosing could repeatedly induce their stimulatory potential. Together, our findings advance understanding of counter-regulatory mechanisms in ACT and highlight the potential of fractionated dosing as a rational strategy to overcome them.

Keywords:  Adoptive cell therapy; CD8+ T cells; Computational biology; Mathematical model; Tumor microenvironment; Tumor-infiltrating myeloid cells

DOI:  https://doi.org/10.1038/s41598-026-50922-3
Cell Stem Cell. 2026 Apr 24. pii: S1934-5909(26)00144-X. [Epub ahead of print]

TCA cycle rewiring underpins histone acetylation sourcing and cell-fate transitions during exit from naive pluripotency.

Eleni Kafkia, David Pladevall-Morera, Lidia Argemi-Muntadas, Gangqi Wang, Roberta Noberini, Arnau Casòliba-Melich, Sandra Bagés-Arnal, Matthias Anagho-Mattanovich, Rita Silvério-Alves, Johanna Gassler, Tiziana Bonaldi, Ton J Rabelink, Thomas Moritz, Jan Jakub Żylicz.

  Metabolism shapes stem cell differentiation and epigenome regulation, especially during the exit from naive pluripotency in vitro. Yet how metabolic networks reorganize at implantation remains unclear. Here, we map metabolite routing in pre- and post-implantation mouse embryos and across dynamic pluripotency transitions in stem cells, revealing that the tricarboxylic acid (TCA) cycle undergoes spatio-temporal rewiring rather than a simple shutdown. Pyruvate emerges as a central metabolic nexus, where pyruvate carboxylase and malic enzyme activities create a cyclical carbon flow essential for balanced metabolic and transcriptional states, timely exit from naive pluripotency, and differentiation. As cells leave naive pluripotency, glutamine increasingly fuels the TCA cycle; unexpectedly, it is also the dominant carbon source for histone acetylation. The necessary acetyl-CoA is generated via IDH1-mediated reductive glutamine carboxylation and is coupled to pyruvate cycling, sustaining histone acetylation. These findings uncover a metabolically rewired, route-specific nutrient utilization program that links metabolism to epigenomic regulation and pluripotency transitions at implantation.

Keywords:  13C isotope tracing; development; differentiation; embryo; epigenetics; histone acetylation; metabolism; pluripotency; spatial metabolomics; stem cells

DOI:  https://doi.org/10.1016/j.stem.2026.04.004
Mol Ther Oncol. 2026 Jun 18. 34(2): 201193

Engineering fratricide-resistant CCR4/CD7 CAR T cells with enhanced safety and persistence for T cell malignancies.

Sile Li, Wenwei Tu, Wing Leung.

DOI: https://doi.org/10.1016/j.omton.2026.201193
Nat Commun. 2026 Apr 27.

Proteasome alteration between epithelial and hematopoietic cells facilitates positive selection of CD8 T cells.

Mami Matsuda-Lennikov, Jamie-Jean De La Torre, Todd Snow, Jacqueline Battaile, Felix Kalle-Youngoue, Alison Jacques, Aya Ushio, Akihide Shimizu, Miho Shinzawa, Christian T Mayer, Parirokh Awasthi, Raj Chari, Izumi Ohigashi, Shigeo Murata, Yousuke Takahama.

The thymoproteasome, a proteolytic complex uniquely expressed in cortical thymic epithelial cells (cTECs), governs the positive selection of CD8 T cells. It has been hypothesized that the thymoproteasome promotes CD8 T cell development by forging a sequential switch in proteasome species between cTECs and medullary antigen-presenting cells (APCs), which generates a stepwise difference in MHC-I-associated peptides between cTECs and medullary APCs, thereby sparing positively selected thymocytes from subsequent negative selection. In this study, we engineer mice ectopically expressing thymoproteasomes in various APCs including medullary TECs (mTECs), eliminating the proposed proteasome switch. Surprisingly, we find that the proteasome switch between cTECs and mTECs is dispensable for thymoproteasome-dependent CD8 T cell development. Instead, we find that ectopic thymoproteasomes in hematopoietic cells impair CD8 T cell development by hindering cortical positive selection. Our findings reveal that the proteasome difference between cTECs and hematopoietic cells in the thymic cortex facilitates thymoproteasome-dependent positive selection.

DOI: https://doi.org/10.1038/s41467-026-72411-x
iScience. 2026 May 15. 29(5): 115593

Activation-gated, T cell-restricted silencing of Dapk1 enhances Bacille Calmette-Guérin-elicited protective CD4+ memory.

Zixuan Liu, Weihuang Liu, Chenyu Zhao, Xuanchang Bai, Fangting Zhou, Hang Sun, Jiahe Shi, Pinru Chen, Min Liu, Qin Pan.

  Durable CD4+ T cell memory is essential against mycobacterial infection, yet activation-induced cell death (AICD) limits the survival of activated clones after BCG vaccination. The upstream, cell-intrinsic brakes that govern this bottleneck remain incompletely defined. Combining transcriptomics, loss-of-function tests, and in vivo engineering, we identify Dapk1 as a pro-apoptotic regulator that is downregulated in memory CD4+ T cells and promotes activation-induced death in T cell models. We develop an activation-gated AAV platform in which an NFAT-IL-2 promoter drives Cre to flip a FLEXed U6-shRNA cassette, and package them into a single AIO vector. This design confines Dapk1 silencing to antigen-experienced T cells, preferentially within the CD4+CD44hi compartment. In BCG-vaccinated mice, transient activation-linked Dapk1 inhibition expands CD4+ TCM cells, enhances IL-2 and Th1-skewed recall responses, lowers pulmonary, and splenic bacterial burdens after M.tb challenge. These findings highlight a strategy to selectively modulate intrinsic death pathways during immune priming for strengthening vaccine-elicited T cell memory.

Keywords:  biological sciences; biotechnology; immunology; molecular biology

DOI:  https://doi.org/10.1016/j.isci.2026.115593
Mol Ther Oncol. 2026 Jun 18. 34(2): 201200

Class I HDAC inhibition enhances the stem-like memory properties of CRISPR-engineered CAR T cells in neuroblastoma.

Dan Cappabianca, Mahmoud Toulany, Seth Zima, Amanda Shea, Jolanta Vidugiriene, Anthony Lauer, Kayla Sylvester, Varun Gnanasekar, Sean Foster, Rithvik Turaga, Krishanu Saha, Jose Ayuso, Quaovi H Sodji.

  Manufacturing chimeric antigen receptor (CAR) T cells with a stem cell memory phenotype can enhance their persistence in patients. Histone deacetylase inhibitors (HDACis) targeting class I HDACs promote chromatin remodeling in virally manufactured CAR T cells, leading to the activation of the Wnt pathway, and ultimately improve CAR T cell persistence. However, it is unknown whether the persistence of CRISPR-engineered CAR T cells can also be enhanced through such HDACi-mediated epigenetic modulation. CAR T cells engineered using CRISPR-Cas9 to integrate a CAR construct into the T cell receptor alpha constant (TRAC) were treated with various class- or isoform-selective HDACis, and phenotypic, functional, and metabolic changes were assessed in vitro and in a GD2+ neuroblastoma xenograft model. Compared to untreated GD2 TRAC-CAR T cells, chidamide and mocetinostat increased the stem cell memory marker expression (CD62L+/CCR7+/IL-7Rα+). Chidamide induced a fragmented mitochondrial morphology and, in vivo, enhanced the persistence and naive phenotype of the GD2 TRAC-CAR T cells without upregulating exhaustion markers (PD-1/LAG3). These findings suggest that in the management of treatment-resistant pediatric solid tumors, utilizing chidamide during the manufacturing of CRISPR-engineered CAR T cells may enhance their persistence while retaining a naive phenotype.

Keywords:  CAR T cells; CRISPR; HDAC inhibitor; MT: Special Issue - Advancements in pediatric cancer therapy; exhaustion; metabolism; mitochondia; neuroblastoma; pre-clinical; stem cell memory

DOI:  https://doi.org/10.1016/j.omton.2026.201200
Cancer Lett. 2026 Apr 28. pii: S0304-3835(26)00311-3. [Epub ahead of print]651 218548

Lactylation of HIF-1α at K172 drives HIF-1 complex assembly to promote hypoxia-induced immune evasion in esophageal squamous cell carcinoma.

Ji Cong, Sujuan Zheng, Haonan Zhang, Yi Li, Zhihua Liu.

Hypoxia is a hallmark of the tumor microenvironment, but its role in immune evasion in esophageal squamous cell carcinoma (ESCC) remains to be fully elucidated. Here, we demonstrate hypoxia inversely correlated with anti-tumor immune signatures and CD8+ T cell infiltration in clinical samples and murine models. Functionally, reducing hypoxia with the agents TH-302 or PX-478 in the AKR model enhanced intratumoral CD8+ T cell infiltration and increased their expression of Granzyme B, IFNγ, and TNFα. Mechanistically, hypoxia-induced immune suppression was dependent on protein lactylation. Inhibiting lactylation reversed the hypoxic suppression of CD8+ T cell function and abrogated the hypoxia-driven transcriptional program, which involved pathways like glycolysis, TGFβ, and Notch signaling. This lactylation-dependent regulation operated by facilitating the formation of the HIF-1 transcription complex. Specifically, mass spectrometry identified lactylation at the K172 site of HIF-1α, which was crucial for its binding to HIF-1β and subsequent target gene activation. Furthermore, in a preclinical ESCC model, pharmacological inhibition of HIF-1α with PX-478 synergized with anti-PD-1 therapy, leading to superior tumor control and enhanced CD8+ T cell cytotoxicity. Our study identifies HIF-1α K172 lactylation as a pivotal mechanism of hypoxia-mediated immune escape in ESCC, suggesting a therapeutic strategy to improve immunotherapy.

DOI: https://doi.org/10.1016/j.canlet.2026.218548
Signal Transduct Target Ther. 2026 Apr 27. pii: 155. [Epub ahead of print]11(1):

Therapeutic targeting of BCL-2 during CART cell production augments potency through non-apoptotic adaptive changes.

Nada S Aboelella, Ryan Park, Erting Tang, Nicholas Asby, Joshua D Ho, Tony Pan, Sidney Wang, Lishi Xie, Justin P Kline, Peter A Riedell, Jun Huang, James L LaBelle.

Targeting the BCL-2 family of proteins, key regulators of cellular apoptosis, with BH3-mimetics has been a major therapeutic goal to overcome cancer cell death resistance. However, beyond their canonical roles in apoptosis, BCL-2 proteins also play vital roles in cellular metabolism, signaling, and, increasingly, immune cell regulation. T cells in particular depend heavily on BCL-2 family proteins during ontogeny and maintenance, yet the broader consequences of pharmacologically inhibiting anti-apoptotic BCL-2 proteins in T cells remain underexplored. Our group has previously demonstrated that BCL-2 inhibition with the BH3-mimetic venetoclax induces gene expression and plasticity changes in murine T cells. Building upon this, we here investigate whether venetoclax-driven T cell reprogramming can be leveraged to enhance adoptive cell therapies, specifically using chimeric antigen receptor (CAR) T cells targeting CD19 as a model system. Our findings reveal that venetoclax treatment during ex vivo expansion of CART cells, prepared from T cells from healthy donors or chemotherapeutically pretreated patients, potently augments antitumor efficacy in a BCL-2-dependent manner. Transcriptomic and functional analyses demonstrate that venetoclax reprograms CART cells by regulating signaling pathways (e.g., IL-2/STAT5 and PI3K/AKT) and metabolic programs (e.g., OXPHOS and glycolysis), yielding CART cells with superior fitness and effector functionalities. These results highlight a novel therapeutic approach using anti-apoptotic drugging to enhance the performance of adoptive T cell therapies and support further examination of venetoclax and other BH3-mimetics as immune modulators.

DOI: https://doi.org/10.1038/s41392-026-02655-y