bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2026–07–26
27 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. In vitro inhibition of STAT5 signaling limits CD8⁺ T cell exhaustion and improves outcomes in adoptive T-cell therapy.
  2. Cystine Restriction Alleviates T Cell Exhaustion and Enhances CAR-T Cell Potency.
  3. Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
  4. Nicotinamide riboside tunes adoptive T cells for memory and metabolic fitness.
  5. Tertiary lymphoid structures harbour stem-like tumour-specific T cells.
  6. Reversal of T cell exhaustion enables cancer vaccine efficacy in BRCA1-deficient ovarian cancer.
  7. E4BP4 restrains effector-memory CD8+ T cell responses in systemic lupus erythematosus.
  8. Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in HIV-1 Infection.
  9. Prohibitin 2 is a key regulator of T cell proliferation, differentiation, and effector functions in vivo.
  10. Reassessment of Hematopoietic Stem Cell Aging through Metabolic Uncoupling and Mitochondrial Resilience.
  11. Immunosenescence in systemic lupus erythematosus: Mechanisms, clinical consequences, and therapeutic implications.
  12. Type I IFN-controlled Qa-2 expression identifies and maps the generation of Eomes+ thymic innate CD8 T cells.
  13. Lipids in ovarian cancer ascites impair T cell activation by disrupting TCR dynamics.
  14. The metabolic roles of immune checkpoint molecules.
  15. A novel peptide-MHC-based T cell engager synergizes with tumor-targeted IL-12 for immunotherapy of solid tumors.
  16. Drug holidays restore exhausted T cell responses to PD1 blockade.
  17. Modulating the VIP-VIPR pathway reprograms CAR T cells for superior antitumor efficacy in preclinical cancer models.
  18. Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.
  19. Parallel 4-1BB Signaling in Dual DLL3/CD56-Targeting CAR-T Cells Triggers Adaptive Proliferation and Functional Persistence to Eradicate Small Cell Lung Cancer.
  20. Efficient generation of human cDC1-like cells to detect and enhance tumor-reactive T cells via CD4+ T cell help.
  21. T cell exhaustion: a two-sided blade in systemic lupus erythematosus, from molecular mechanisms to clinical translation.
  22. Decoding the tumor-aging axis: from bench to clinical.
  23. The mechanism of macrophage glycolysis regulating Th17 cell differentiation and promoting the progression of EAN mice.
  24. Combination of exosome vaccines, lenvatinib, and anti-PD-1 eradicates tumor in autochthonous hepatocellular carcinoma mice.
  25. Targeting the CD31 immunometabolic axis: Precision strategies for modulating T cell activation, migration, and autophagy.
  26. Endothelial cell-intrinsic NOD2 signaling regulates the intestinal immune response through the generation of effector and memory T cells.
  27. Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.
  1. Cancer Immunol Res. 2026 Jul 22.
    In vitro inhibition of STAT5 signaling limits CD8⁺ T cell exhaustion and improves outcomes in adoptive T-cell therapy.
    Mitra Shourian, Benoîte Bourdin, Nehme El-Hachem, Clémence Ruisseaux, Alexis Vallée, Arnau Ballestero Vidal, Olivier Gingras, Hugo Roméro, Edward O Kwarteng, Élie Haddad, Vincent-Philippe Lavallée, Jean-Christophe Beltra, Hélène Decaluwe.
      T cell exhaustion remains a barrier to adoptive cell therapies. Although γc cytokines are used to expand T cells, their impact on T cell states remains incompletely defined. Using an in vitro model of repetitive TCR stimulation, we found that high-dose IL-2 or IL-15 promoted exhausted CD8⁺ T cell (TEX) differentiation, with increased inhibitory receptor expression and loss of stem-like features. During chronic LCMV Clone 13 infection, high IL2Rβ expression marked virus-specific CD8⁺ T cells with features of terminally exhausted TEX cells, whereas IL2Rβ deficiency favored progenitor-like populations. In TEX cells, IL-2 and IL-15 preferentially induced STAT5 phosphorylation over other signaling pathways. Genetic disruption of STAT5 similarly supported progenitor subsets, implicating STAT5 in the progression toward more differentiated TEX states under chronic stimulation. We therefore asked whether transient STAT5 attenuation during in vitro T cell expansion could bias differentiation toward progenitor-like populations without compromising functional competence. Transient JAK3 or STAT5 inhibition enriched TCF1⁺Ly108⁺ progenitor-like cells while preserving cytokine production and degranulation capacity. Following transfer into tumor-bearing mice, cells expanded under STAT5-inhibited (STAT5i) conditions mediated superior tumor control and prolonged survival. Likewise, transient STAT5 inhibition preserved memory-progenitor phenotypes in human CD22 CAR T cells without impairing cytotoxicity. RNA sequencing of STAT5i-expanded CD8⁺ T cells confirmed reinforced stem-like transcriptional programs and reduced enrichment of effector and exhausted signatures. Together, these findings identify the IL-2Rβ-STAT5 axis as a regulator of CD8⁺ T cell differentiation and support transient STAT5 modulation during ex vivo expansion to improve therapeutic T cell products.
    DOI:  https://doi.org/10.1158/2326-6066.CIR-25-1493
  2. Cancer Res. 2026 Jul 21.
    Cystine Restriction Alleviates T Cell Exhaustion and Enhances CAR-T Cell Potency.
    Xiaoxue Pan, Yuhang Yin, Haopeng Hong, Jichang Li, Jing Zhu, Xin Wang, Yucun Liu, Pengyuan Wang, Shanwen Chen.
      While chimeric antigen receptor (CAR) T cell therapy has demonstrated significant efficacy in treating hematological malignancies, its application in solid tumors remains challenging. A major limitation of CAR-T cell efficacy in solid tumors is the functional exhaustion of CD8⁺ T cells. Here, we investigated metabolic regulators of CD8⁺ T cell exhaustion, identifying that cystine promotes CD8+ T cell exhaustion. RNA sequencing analysis of an in vitro exhaustion model revealed that SLC7A11 was significantly upregulated in exhausted CD8⁺ T cells. A monoclonal antibody specifically targeting SLC7A11 was subsequently generated, and its binding affinity was rigorously validated. Single-cell RNA sequencing and functional studies demonstrated that inhibition of SLC7A11 promoted the expansion of CD8⁺ stem-like memory T cells and alleviated T cell exhaustion. In vivo, treatment with the anti-SLC7A11 antibody enhanced the antitumor efficacy of CAR-T cells. Mechanistically, SLC7A11 inhibition suppressed cystine uptake, which activated the GCN2-eIF2α-SLC1A5 signaling axis. Upregulation of SLC1A5 increased glutamine uptake to stimulate oxidative phosphorylation and support mitochondrial fitness. Together, these findings demonstrate that cystine restriction alleviates CD8+ T cell exhaustion and enhances the efficacy of CAR-T cell therapy.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-4375
  3. Immunometabolism (Cobham). 2026 Jul;8(3): e00086
    Lipid-driven epigenetic exhaustion: linking palmitate metabolism to CD8+ T-cell dysfunction in cancer.
    Desh Raj, Mahesh Kathania, Tuoqi Wu, Arianne L Theiss, K Venuprasad.
      In a recent study published in Science Immunology, Tiberti and colleagues demonstrate that palmitate, a saturated fatty acid enriched in tumors, directly impairs CD8+ cytotoxic T lymphocyte function through mitochondrial and epigenetic reprogramming. Palmitate exposure reduced mitochondrial fitness, oxidative phosphorylation, and adenosine triphosphate production, resulting in defective proliferation, cytokine production, and antitumor activity. Mechanistically, mitochondrial dysfunction decreased intracellular acetyl-CoA availability, leading to reduced histone acetylation and loss of chromatin accessibility at loci that control effector programs. The study further identifies sphingosine kinase 2 as a critical mediator of lipid-induced dysfunction. Importantly, SPHK2 inhibition restored mitochondrial function, histone acetylation, and cytotoxic T lymphocyte antitumor activity, highlighting a potential therapeutic strategy for enhancing cancer immunotherapy.
    Keywords:  T-cell exhaustion; acetyl CoA; cytotoxic T cells; palmitate
    DOI:  https://doi.org/10.1097/IN9.0000000000000086
  4. Mol Ther. 2026 Jul 21. pii: S1525-0016(26)00581-2. [Epub ahead of print]
    Nicotinamide riboside tunes adoptive T cells for memory and metabolic fitness.
    Zhenyu Dai.
      
    DOI:  https://doi.org/10.1016/j.ymthe.2026.07.010
  5. Nature. 2026 Jul 22.
    Tertiary lymphoid structures harbour stem-like tumour-specific T cells.
    Alexander B Afeyan, Adi Nagler, Chloe R Tu, Gabriel Roberti De Oliveira, Berkay Simsek, Maxwell D Seager, Nourhan El Ahmar, Haley E Sax, Emma Lin, Amit Sud, Mehdi Borji, Cleo Forman, Sophia Liu, Patrick A Ott, Toni K Choueiri, Jennifer G Abelin, Richard Burack, Shuqiang Li, Kenneth J Livak, Svitlana Tyekucheva, Derin B Keskin, Fei Chen, Michael B Atkins, Jeremy M Simon, Sabina Signoretti, Giacomo Oliveira, David A Braun, Catherine J Wu.
      Tertiary lymphoid structures (TLSs) are associated with improved responses to immune checkpoint blockade across solid tumours1,2, but how they impact the phenotypic properties of tumour-specific T cells remains unclear. Here we found, across 24 treatment-naive renal cell carcinoma (RCC) tumours, that TLS-containing tumours are more heavily infiltrated by exhausted CD8+ T cells and have a reduced terminal exhaustion transcriptional program compared with TLS- tumours. Specificity screening of 554 T cell clonotypes expanded within the microenvironment of 6 RCC tumours revealed 82 TCRs that were reactive against tumour cells and/or RCC antigens. A subset of tumour-specific T cell clonotypes (12%) was enriched within TLSs, and these expressed an increased program of stem-like progenitor exhaustion, associated with favourable anti-tumour immunity. However, in 60 independent RCC tumours, macrophages within tumour margins of TLS-containing tumours had an inferred immunosuppressive phenotype and were colocalized with exhausted putative tumour-reactive T cells in a subgroup that was further analysed, therefore supporting this mode of immune evasion as a counterbalance to T cell immune pressure. Our data reveal that TLSs are reservoirs of tumour-specific T cells with stem-like progenitor features that could be leveraged by T cell immunotherapies.
    DOI:  https://doi.org/10.1038/s41586-026-10808-w
  6. iScience. 2026 Jul 17. 29(7): 116587
    Reversal of T cell exhaustion enables cancer vaccine efficacy in BRCA1-deficient ovarian cancer.
    Laurent Beziaud, Aspram Minasyan, Cheryl L-L Chiang, Rania M Soukarieh, Matilde M Coppi, Raphaël Rovelli, Jonathan Thevenet, Stephanie Tissot, Denarda Dangaj-Laniti, Lana E Kandalaft.
      BRCA mutations in ovarian cancer (OC) are associated with increased tumor-infiltrating lymphocytes and inflammatory features, yet immunotherapy for OC has shown limited efficacy. Using the ID8 mouse model, we discovered that Brca1 deficiency-but not Brca2-impairs the effectiveness of a dendritic cell-based cancer vaccine (OCDC). OCDC vaccine reduced tumor growth and improved survival in mice bearing Trp53 -/- and Trp53 -/- Brca2 -/- tumors but was ineffective against Trp53 -/- Brca1 -/- tumors. Transcriptomic analysis revealed metabolic and immunologic reprogramming in OCDC-responsive tumors, whereas Brca1 -/- tumors remained refractory. Vaccine inefficacy was associated with a pre-existing inflamed microenvironment, enriched in activated yet exhausted T cells, limiting further immune stimulation by vaccination. Combining OCDC with anti-VEGF and PARP inhibitors partially restored vaccine efficacy in Brca1 -/- tumors, while addition of anti-PD-1 further enhanced T cell function and promoted long-term survival. These findings highlight BRCA1's role in cancer vaccine sensitivity and support rational combination immunotherapies for BRCA1-mutated OC.
    Keywords:  BRCA1 mutation; PARP inhibition; T cell exhaustion; cancer vaccine; immune checkpoint blockade; ovarian cancer
    DOI:  https://doi.org/10.1016/j.isci.2026.116587
  7. Autoimmunity. 2026 Dec 31. 59(1): 2702524
    E4BP4 restrains effector-memory CD8+ T cell responses in systemic lupus erythematosus.
    Ming Zhu, Suqing Zhou, Changxing Gao, Yanshan Zhu, Xieling He, Qianjin Lu, Ming Zhao, Zijun Wang.
      Increasing evidence shows that CD8+ T cells are the pathogenic mediators of tissue injury in systemic lupus erythematosus (SLE), sustaining the chronic inflammation through the accumulation of long-lived cytotoxic memory populations. However, the transcriptional mechanisms that prevent the aberrant differentiation of pathogenic CD8+ T cells remain poorly understood. Here, the transcription factor E4BP4 (NFIL3) was identified as a critical restraint of cytotoxic effector-memory CD8+ T cells in lupus. E4BP4 expression was reduced in CD8+ T cells from SLE patients and inversely correlated with disease activity. Using a lupus-like disease model, we found that E4BP4 deficiency accelerated disease progression, resulting in heightened autoantibody production, immune complex deposition, and renal pathology. This phenotype was associated with the systemic accumulation of cytotoxic effector-memory CD8+ T cells. Depletion of CD8+ T cells significantly ameliorated the disease phenotype, confirming the functional contribution of CD8+ T cells to lupus-like immunopathology. Competitive adoptive transfer experiments revealed that E4BP4 functions cell-intrinsically to limit the cytotoxicity and proliferation of CD8+ T cells in autoimmunity. Beyond autoimmunity, E4BP4 deficiency also resulted in an exuberant CD8+ effector-memory T cell response to Listeria monocytogenes infection, indicating a broader role for E4BP4 in limiting CD8+ T cell effector-memory responses. Collectively, these findings establish E4BP4 as a transcriptional checkpoint that restricts pathogenic CD8+ effector-memory T cell responses to maintain immune homeostasis in autoimmunity and infection.
    Keywords:  E4BP4; Systemic lupus erythematosus; cytotoxicity; effector-memory CD8+ T cells; immunological checkpoint
    DOI:  https://doi.org/10.1080/08916934.2026.2702524
  8. JCI Insight. 2026 Jul 21. pii: e204383. [Epub ahead of print]
    Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in HIV-1 Infection.
    Amanda Cabral da Silva, Luke Flantzer, Jaclyn Weinberg, Shuya Kyu, Lisa P Daley-Bauer, Anyce Godoy, Ana Carolina Santana, Aarthi Talla, Amber Rittgers, Sarah Welbourn, David E Gordon, Jeffrey A Tomalka, Vincent C Marconi, Dean P Jones, Souheil-Antoine Younes.
      The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4⁺ T-cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4⁺ T-cell metabolic and functional states. Among these, p-cresol sulfate (PCS) emerged as a mechanistic prototype. Ex vivo flow cytometry and single-cell RNA sequencing of CD4⁺ T-cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation, regulatory-like identity, and cellular senescence. In vitro transcriptomic and proteomic analyses of PCS-exposed CD4⁺ T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic findings with HIV-1 reservoir measurements revealed that CD4⁺ T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. These findings define a microbiome-derived axis that reshapes CD4⁺ T-cell metabolism and fate, promotes immune aging in PLWH, and may foster immunometabolic states linked to long-term HIV-1 reservoir persistence.
    Keywords:  AIDS/HIV; Adaptive immunity; Aging; Cellular senescence; Immunology; Metabolomics
    DOI:  https://doi.org/10.1172/jci.insight.204383
  9. Commun Biol. 2026 07 20. pii: 989. [Epub ahead of print]9(1):
    Prohibitin 2 is a key regulator of T cell proliferation, differentiation, and effector functions in vivo.
    Johannes F Vogt, Carsten Merkwirth, Petra Adams-Quack, Elena Zurkowski, Emmanouill Stylianakis, David C Uhlfelder, Thomas Michna, Assel Nurbekova, Ute Distler, Liliana Rojas-Charry, Hajime Yurugi, Sonja Reißig, F Thomas Wunderlich, Krishnaraj Rajalingam, Stefan Tenzer, Axel Methner, Thomas Langer, Ari Waisman, Nadine Hövelmeyer.
      Prohibitin 2 (PHB2) is a highly conserved protein with essential roles in cell homeostasis and survival across different cell types. Previous studies have shown that the deletion of PHB2 results in an arrest in proliferation due to impaired mitochondrial function regulated by the dynamin-like GTPase OPA1. The function of PHB2 in immune cells remains unclear; however, some studies suggest that PHB2 plays a role in the cell membranes of B and T cells. In order to elucidate the role of PHB2 in immune cells, we generated PHB2-deficient T cells. Our findings reveal a pivotal role for PHB2 in the proliferation and differentiation of T cells. PHB2 deficiency inhibits T cell proliferation by inducing a cell cycle arrest at the G1 to S phase, thereby preventing the differentiation into effector T cells. Furthermore, in contrast to previous reports, T cells lacking PHB2 are more resistant to apoptosis. Metabolic analysis reveals that PHB2-deficient T cells fail to boost their energy production through glycolysis and oxidative phosphorylation upon activation, hindering their ability to sustain biosynthetic processes and to proliferate in response to activation.
    DOI:  https://doi.org/10.1038/s42003-026-10522-3
  10. Exp Hematol. 2026 Jul 22. pii: S0301-472X(26)00118-9. [Epub ahead of print] 105485
    Reassessment of Hematopoietic Stem Cell Aging through Metabolic Uncoupling and Mitochondrial Resilience.
    Chong Yang, Keiyo Takubo, Toshio Suda.
      Hematopoietic stem cell (HSC) aging is often described as a gradual loss of stem cell fitness that culminates in impaired blood production, immune dysfunction, and increased susceptibility to hematologic disease. However, recent work suggests that this view is too simple. Rather than a uniform decline, aging appears to remodel the HSC compartment into metabolically and functionally distinct states, including maladaptive trajectories as well as surprisingly resilient subsets. In this review, we argue that HSC aging is best understood through the interplay of mitochondrial regulation, metabolic uncoupling, and niche-derived stress, with particular emphasis on how recent findings revise several longstanding assumptions in the field (Box 1).
    Keywords:  HSC aging; Hematopoietic resilience; Metabolic uncoupling; Mitochondrial metabolism; Niche
    DOI:  https://doi.org/10.1016/j.exphem.2026.105485
  11. Autoimmun Rev. 2026 Jul 24. pii: S1568-9972(26)00158-8. [Epub ahead of print] 104144
    Immunosenescence in systemic lupus erythematosus: Mechanisms, clinical consequences, and therapeutic implications.
    José Pedro Duarte Hillal, Thaina Affeldt Weber, Henrique Luiz Staub, Moises Evandro Bauer.
      Systemic lupus erythematosus (SLE) is an autoimmune disease associated with chronic immune dysregulation across the lifespan. Accumulating evidence suggests that many immunological alterations observed in SLE resemble those seen in physiological aging. Here, we review the major innate and adaptive mechanisms of immunosenescence in SLE, including telomere shortening, chronic low-grade inflammation, thymic dysfunction, and the expansion of senescent immune cell subsets. Of note, we discuss how these age-associated immune phenotypes emerge early and contribute to disease activity, organ damage, and long-term outcomes. Clinically, immunosenescence contributes to cardiovascular complications, frailty, increased infections, and cognitive impairment in SLE. Therapies targeting senescence-related pathways - including modulation of intracellular metabolic pathways and senolytics - are also discussed and constitute promise as emerging strategies.
    Keywords:  Aging; Autoimmunity; Cytokines; Immune senescence; T cells
    DOI:  https://doi.org/10.1016/j.autrev.2026.104144
  12. iScience. 2026 Jul 17. 29(7): 116530
    Type I IFN-controlled Qa-2 expression identifies and maps the generation of Eomes+ thymic innate CD8 T cells.
    Hee Yeun Won, Min-Kyung Joo, Dominic Lanasa, Changwan Hong, Jung-Hyun Park.
      Innate CD8 T cells are a subset of CD8 lineage T cells that acquire proinflammatory effector functions during their development in the thymus. Yet the developmental mechanisms diverting them from conventional CD8 T cells remain incompletely understood. By mapping their developmental trajectory in the thymus, here we identify high-level expression of the nonclassical MHC-I molecule Qa-2 as a surface marker of innate CD8 T cells. Because Qa-2 expression is induced by type I interferon (IFN) signaling, these results further led us to uncover a role for tonic type I IFN signaling in their generation. Accordingly, interleukin-4 is considered both necessary and sufficient for this process, but innate CD8 T cell differentiation was also markedly impaired in the absence of type I IFN signaling, as documented with genetically engineered mice. Altogether, these findings report an intrathymic cytokine circuitry that orchestrates the differentiation of innate CD8 T cells during their thymic development.
    Keywords:  IFNAR; IFNγ; eomesodermin; thymus; γc
    DOI:  https://doi.org/10.1016/j.isci.2026.116530
  13. Nat Metab. 2026 Jul;8(7): 1508-1527
    Lipids in ovarian cancer ascites impair T cell activation by disrupting TCR dynamics.
    Erica G Brown, Ewoud B Compeer, Zhiyang Gan, Andre R Kelly, Alexander A Shestov, Laura Córdoba-Espejo, Mitchell T Evans, Alan Y Liu, Noelle H Naughton, Tanay S Parnaik, Jemma H Larson, Bruce R Blazar, Caroline R Bartman, Joshua D Rabinowitz, Michael L Dustin, Daniel J Powell, Roddy S O'Connor.
      T cell-based therapies have limited success against ovarian cancer for poorly understood reasons. Here we show that lipids in ovarian cancer ascites fluid disrupt nanoscale T cell receptor dynamics-driven T cell activation. T cells stimulated in ascites of patients with ovarian cancer have an altered lipid profile, including changes in phosphatidylcholine (PC) and phosphatidylethanolamine content, and disrupted membrane properties. Using untargeted lipidomics, we reveal which lipid species are consumed by T cells in ascites and show that 18:0-18:2 PC impairs T cell activation at physiological concentrations. Mechanistically, we uncover that lipids in ascites, including 18:0-18:2 PC, disrupt nanoscale T cell receptor clustering in immunological synapses. Importantly, pre-activated T cells overcome these lipid-induced barriers, highlighting a promising strategy to enhance adoptive T cell-based therapies for ovarian cancer. These findings provide mechanistic insights into lipid-mediated immune suppression in the tumour microenvironment and an actionable strategy to overcome these barriers.
    DOI:  https://doi.org/10.1038/s42255-026-01557-1
  14. Endocr Rev. 2026 Jul 21. pii: bnag030. [Epub ahead of print]
    The metabolic roles of immune checkpoint molecules.
    Yan Wang, Junxue Wang, Sijia Dan, Junke Zheng, Yingli Lu, Fangzhen Xia.
      Immune checkpoint molecules (ICMs) are a class of surface proteins predominantly expressed on immune cells that play a key role in maintaining immune homeostasis by regulating the functions of T cells and other immune cells. Beyond their established immunoregulatory roles, emerging evidence indicates that ICMs are also involved in metabolic regulation. Within the tumor microenvironment (TME), tumour-derived ICMs have been shown to modulate glucose, amino acid, and lipid metabolism in infiltrating T cells, thereby influencing their metabolic reprogramming and functional states. Certain ICMs expressed on immune cells may directly regulate systemic metabolism through cell-intrinsic, immune-independent mechanisms. Moreover, specific ICMs are constitutively expressed in key metabolic tissues, such as pancreatic islets, liver, and adipose tissue, where they are thought to contribute to the maintenance of systemic metabolic homeostasis. Clinically, host metabolic status can affect the efficacy of immune checkpoint inhibitor (ICI) therapies. Conversely, ICI treatment can lead to metabolism-related adverse effects, such as ICI-associated diabetes (ICI-DM), which may extend beyond classic autoimmune insulin-dependent diabetes. Accumulating evidence suggests that ICMs can exert direct regulatory roles in metabolism independent of their canonical immune functions. Elucidating how ICMs regulate metabolism could, on the one hand, improve ICI therapy by maintaining metabolic homeostasis and preventing T cell exhaustion, and on the other hand, facilitate the development of novel therapeutic strategies for metabolic diseases that simultaneously target metabolic and inflammatory pathways. This review synthesises current knowledge on the metabolic roles and regulatory mechanisms of ICMs.
    Keywords:  Crosstalk; ICI therapy; Immune checkpoint molecules; Metabolic disorders; Metabolism
    DOI:  https://doi.org/10.1210/endrev/bnag030
  15. Int Immunopharmacol. 2026 Jul 22. pii: S1567-5769(26)01000-3. [Epub ahead of print]186 117154
    A novel peptide-MHC-based T cell engager synergizes with tumor-targeted IL-12 for immunotherapy of solid tumors.
    Shihui Wang, Qing Xu, Xueqian Peng, Xinman Li, Tianqing Zheng.
      Conventional CD3-targeting bispecific T cell engagers (BiTEs) have shown limited efficacy in solid tumors, largely due to the highly immunosuppressive tumor microenvironment (TME) and systemic T cell activation-associated toxicity. To address this challenge, we developed a peptide-MHC class I-based T cell engager platform that selectively redirects a specific subset of CD8+ T cells to tumor cells. Using the model ovalbumin (OVA) system, we engineered fusion proteins comprising an OVA peptide-H-2Kᵇ complex linked to an anti-HER2 nanobody (OVA-αHER2), enabling simultaneous engagement of OVA-specific T cells and HER2-expressing tumor cells and inducing potent tumor cell killing in vitro. To overcome the immunosuppressive TME, we further combined a HER2-targeted IL-12 fusion protein with OVA-αHER2, achieving synergistic anti-tumor responses in a mouse B16-HER2 solid tumor model. This treatment enhanced both systemic and intratumoral OVA-specific CD8+ T cell responses, accompanied by increased IFN-γ production in the TME. Together, these findings establish a modular immunotherapy strategy that integrates recruitment of a specific CD8+ T cell subset with localized cytokine-mediated immune reprogramming, providing a potential approach for HER2-positive solid tumors.
    Keywords:  Antibody engineering; Cancer immunotherapy; Peptide MHC; Solid tumor; T cells; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.intimp.2026.117154
  16. Nat Rev Immunol. 2026 Jul 21.
    Drug holidays restore exhausted T cell responses to PD1 blockade.
    Chih-Wei Chu, Kenneth Hu.
      
    DOI:  https://doi.org/10.1038/s41577-026-01343-w
  17. Sci Transl Med. 2026 Jul 22. 18(859): eadt9565
    Modulating the VIP-VIPR pathway reprograms CAR T cells for superior antitumor efficacy in preclinical cancer models.
    Heather K Lin, Dejah A Blake, Ruby Freeman, YuJie Chen, Jaehoon Kim, Andrew M Johnson, Kory Wells, Abhijay Mudigonda, William Liu, Poonam Yadav, Fanyuan Zeng, Abir Muhuri, Kiyoon Min, Srijon Sarkar, Yuou Wang, Subir Goyal, Ronald Christopher Roberts, Elyse Christensen, Antonio B Ward, Brad Heller, Paul Chun, Jodi Dougan, Christopher C Porter, Benjamin G Barwick, Chrystal M Paulos, Lily Yang, Anupam Patgiri, Susan Napier Thomas, Edmund K Waller, Sarwish Rafiq.
      Clinical efficacy with chimeric antigen receptor (CAR) T cells is currently limited by numerous factors including poor initial product phenotypes and lack of engagement of endogenous immunity. Vasoactive intestinal peptide (VIP) is an immunosuppressive neuropeptide, and the antagonism of its receptor (VIPR) on T cells potentiates T cell activation. We demonstrated that VIP suppresses CAR T cell function and engineered CAR T cells to secrete a short peptide drug that antagonizes VIPR (CAR/VIPRa). Armored CAR/VIPRa T cells maintained a memory phenotype and were metabolically quiescent after manufacturing yet mounted a strong bioenergetic response after antigen stimulation. Moreover, CAR/VIPRa T cells potentiated endogenous antitumor immunity through the recruitment of host T cells. In syngeneic and xenogeneic mouse models of hematological and solid tumors, CAR/VIPRa T cells exhibited greater tumor infiltration and maintained a less exhausted memory phenotype, resulting in superior antitumor efficacy. Together, these data show that VIPRa peptides produced by armored CAR T cells can enhance T cell function and boost endogenous immunity, thereby improving tumor control.
    DOI:  https://doi.org/10.1126/scitranslmed.adt9565
  18. Smart Med. 2026 Jun;5(3): e70043
    Nuclear-Mitochondria Crosstalk in Senescent Adipose-Derived Stem Cells.
    Yixiang Zhang, Yawei Du, Shifeng Ling, Hanqi Wang, Jiahao He, Jiahong Li, Kaifeng Huo, Baikun Liu, Qingfeng Li, Jiao Wei, Wenguo Cui.
      Adipose-derived stem cells (ADSCs) are central regulators of adipose tissue homeostasis and regenerative capacity. Accumulating evidence indicates that aging and obesity profoundly impair ADSC function, through progressive mitochondrial dysfunction and disrupted mitochondrial-nuclear communication. Emerging studies reveal that defects in nuclear-mitochondrial crosstalk constitute a key driver of ADSC senescence and adipose tissue aging. In this review, we synthesize recent advances in understanding the mitochondrial mechanisms underlying ADSC aging, with particular emphasis on how mitochondrial dysfunction reshapes stem cell fate decisions, metabolic plasticity, and inflammatory signaling within aged adipose niches. We further highlight mitochondria targeting therapeutic strategies that hold promise for reversing ADSC senescence. Collectively, this framework positions mitochondrial regulation as a unifying axis for ADSC rejuvenation, offering new opportunities to restore adipose tissue homeostasis and mitigate age-related metabolic dysfunction.
    Keywords:  adipose derived stem cell; aging; cellular communication; mitochondria; mtDNA
    DOI:  https://doi.org/10.1002/smmd.70043
  19. Cancer Res. 2026 Jul 23.
    Parallel 4-1BB Signaling in Dual DLL3/CD56-Targeting CAR-T Cells Triggers Adaptive Proliferation and Functional Persistence to Eradicate Small Cell Lung Cancer.
    Yan-Na Lei, Diyuan Qin, Yan He, Pei Shu, Benxia Zhang, Yue Chen, Ning Liu, Xia He, Yu-Gu Zhang, Meng-Yao Chang, Xiaoyu Li, Fu-Chun Guo, Liang-Liang Bai, Mingyang Feng, Fu-Jue Wang, Yu Gao, Bo Zhu, ZhongJun Li, Dan Li, Yong-Sheng Wang, Yuquan Wei.
      Limited intratumoral persistence and insufficient proliferative capacity severely restrict the efficacy of chimeric antigen receptor (CAR)-T cell therapies in solid tumors. Here, we demonstrated that DLL3-targeting CAR-T cells co-expressing a CD56 chimeric switch receptor (CSR) and incorporating parallel 4-1BB costimulatory signaling (DBBζ.CBB) effectively address these limitations. In preclinical small cell lung cancer (SCLC) models, DBBζ.CBB exhibited sustained tumor infiltration, prolonged persistence, and superior antitumor activity. Mechanistically, parallel 4-1BB signaling dynamically programed CAR-T cell fate by promoting early expansion and memory maintenance, driving a highly proliferative effector state at the intermediate stage, and delaying terminal exhaustion at the later stage, thereby sustaining in vivo persistence and enabling durable antitumor responses. Building upon the intratumoral T-cell pool established by DBBζ.CBB, subsequent DLL3 trispecific T-cell engager (TriTCE) administration synergistically enhanced tumor eradication by further boosting CD8+ T cell infiltration and overall activation while mitigating exhaustion and terminal differentiation. Collectively, these findings establish a clinically translatable combinatorial framework to enhance the efficacy and durability of CAR-T therapy in solid tumors.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-5261
  20. Cell Rep Methods. 2026 Jul 22. pii: S2667-2375(26)00234-1. [Epub ahead of print] 101533
    Efficient generation of human cDC1-like cells to detect and enhance tumor-reactive T cells via CD4+ T cell help.
    Yizhi Wang, Xin Lei, Tom de Wit, Ellen Schrama, Marij J P Welters, Karel van Leeuwen, Sander de Kivit, Miriam de Boer, Jitske van den Bulk, Noel F C C de Miranda, Ton N Schumacher, Chong Sun, Jannie Borst, Yanling Xiao.
      Classical type 1 dendritic cells (cDC1s) are crucial to anti-tumor immunity by cross-presenting tumor antigens and priming cytotoxic CD8+ T lymphocytes (CTLs). Licensing via CD4+ T cell help endows cDC1s with enhanced cross-presentation and CTL-priming capacity, making them a promising tool to improve adoptive T cell therapies. However, the scarcity of primary human cDC1s limits their in-depth translational investigation and application. Here, we describe a method to efficiently generate DCs in vitro from CD34+c-KIT+ progenitors in non-mobilized peripheral blood. This DC population is enriched for cDC1-like cells that respond to CD4+ T cell help by upregulation of key molecules involved in antigen cross-presentation and T cell costimulation. Upon CD4+ T cell-mediated licensing, the progenitor-derived DC promotes tumor-specific CTL priming and facilitates detection of rare tumor antigen-specific CD8+ T cells in blood and tumor tissues. This DC culture platform incorporating CD4+ T cell help provides a scalable system for immunomonitoring and optimizing adoptive T cell therapies in cancer.
    Keywords:  CP: cancer biology; CP: immunology; adoptive cell therapy; blood progenitor; cDC1-licensing; cDC1-like cell generation; tumor antigen-specific CTL
    DOI:  https://doi.org/10.1016/j.crmeth.2026.101533
  21. Front Immunol. 2026 ;17 1871551
    T cell exhaustion: a two-sided blade in systemic lupus erythematosus, from molecular mechanisms to clinical translation.
    Yanwei Bi, Feifeng Wu, Jueyi Mao, Tasnim Azad, Pengcheng Liu, Xin Zhou, Haotian Xie, Kimsor Hong, Xinying Qiu, Binbin Li, Miaomiao Wu, Liang Zhang, Jidong Tian, Chuan Wen.
      Dysregulated immune responses and extensive inflammatory damage to several organs are hallmarks of systemic lupus erythematosus (SLE), a highly heterogeneous systemic autoimmune disease that significantly impairs patients' quality of life and prognosis. Persistent antigenic stimulation causes T cell exhaustion (Tex), a unique functional state that is carefully controlled by exogenous, temporal, and spatial factors. Tex plays a special bidirectional regulatory role in SLE: on the one hand, it exerts a protective effect by suppressing the excessive activation of autoreactive T cells, thereby mitigating immune-mediated damage to target organs; on the other hand, abnormal exhaustion of specific T cell subsets leads to a loss of immunoregulatory function and may even promote the secretion of pro-inflammatory cytokines, thereby exacerbating pathological damage. Therapeutic strategies based on this dual mechanism focus on restoring immune homeostasis by enhancing protective exhaustion and inhibiting pathogenic exhaustion processes; this can be achieved through precise regulation of exhausted T cell subsets, improvement of the immune microenvironment, and interventions targeting key signalling pathways. This article provides a systematic review of the core molecular mechanisms and phenotypic characteristics of Tex, highlighting the latest research advances regarding its bidirectional regulatory role in SLE, and discusses in detail relevant diagnostic biomarkers and potential targeted therapeutic strategies. It aims to provide new insights and a theoretical basis for the clinical assessment, personalised treatment, and targeted drug development of SLE.
    Keywords:  T cell exhaustion; autoimmune diseases; bidirectional regulation; systemic lupus erythematosus; targeted therapy
    DOI:  https://doi.org/10.3389/fimmu.2026.1871551
  22. Front Immunol. 2026 ;17 1823423
    Decoding the tumor-aging axis: from bench to clinical.
    Yuxin Wang, Guitong Lv, Xinyue Gao, Zheng Jin, Jiani Huang, Zhongyu Wang.
      Population aging is a major global health challenge and a principal risk factor for cancer. Aging does not simply increase mutational burden; it reshapes tissue homeostasis across genetic, epigenetic, metabolic, immune, and systemic dimensions. Genomic instability, epigenetic drift, mitochondrial dysfunction, and metabolic rewiring collectively establish a tumor-permissive landscape that enhances clonal diversification and lowers the threshold for malignant transformation. Concurrently, accumulation of senescent cells and the senescence-associated secretory phenotype (SASP) remodel the microenvironment, promote immune suppression, and weaken tumor surveillance, further exacerbated by immunosenescence and gut microbiota dysbiosis. Importantly, cancer progression feeds back to accelerate organismal aging. Tumor burden and therapy-induced stress destabilize hematopoietic and non-hematopoietic stem cell niches, disrupt systemic metabolic homeostasis, and induce neuroendocrine reprogramming, thereby amplifying multi-organ functional decline. Aging and cancer therefore constitute a bidirectional and self-reinforcing network rather than a linear cause-effect relationship. In this review, we synthesize mechanistic, clinical, and translational evidence defining the tumor-aging axis and discuss emerging strategies aimed at interrupting this pathogenic cycle.
    Keywords:  aging and cancer; cellular senescence; immunosenescence; senescence-associated secretory phenotype; tumor-aging axis
    DOI:  https://doi.org/10.3389/fimmu.2026.1823423
  23. Int Immunopharmacol. 2026 Jul 24. pii: S1567-5769(26)01008-8. [Epub ahead of print]187 117162
    The mechanism of macrophage glycolysis regulating Th17 cell differentiation and promoting the progression of EAN mice.
    Shuping Liu, Huiying Lu, Yuge Kang, Qian Cao, Miao Liu, Zuneng Lu.
      This study investigates how macrophage glycolysis interacts with CD4+ T cells to drive experimental autoimmune neuritis (EAN) progression. In EAN mice, expression of key glycolytic genes (LDHA, GLUT1, HK2, and PKM2) was gradually upregulated in splenic macrophages and sciatic nerve. By the disease peak (day 18 p.i.), these genes reaching approximately 4-to-8-fold increase over controls, paralleling a continuous expansion of the splenic M1 macrophage population. Crucially, in vivo glycolysis inhibition via 2-deoxyglucose (2-DG) effectively suppressed splenic M1 polarization and sciatic nerve CD86 IHC intensity, thereby mitigating EAN clinical scores from day 10 onward. Further in vitro experiments revealed that M1-polarized macrophages exhibited significantly enhanced glycolytic activity, characterized by increased glucose uptake, ATP generation, and lactate secretion. Their conditioned medium successfully drove CD4+ T cell differentiation into the Th17 subset, upregulating RORγt expression and the secretion of IL-17 and IL-22. Mechanistically, extracellular lactate promoted Th17 differentiation by facilitating PKM2 nuclear translocation, which enhanced STAT3 phosphorylation and RORγt expression while reciprocally suppressing Foxp3. Genetically overexpressing PKM2 augmented lactate-induced Th17 cytokine secretion, whereas pharmacological stabilization of PKM2 tetramers via TEPP-46 blocked its nuclear entry and reduced Th17 differentiation. Ultimately, targeted in vivo intervention with TEPP-46 significantly improved neurological function scores in EAN mice, accompanied by diminished Th17 cell infiltration and alleviated inflammatory demyelination. Together, our findings elucidate the "macrophage glycolysis-lactate-PKM2" axis in regulating Th17 differentiation, offering a novel metabolic-immune therapeutic strategy for EAN and its clinical counterpart, acute inflammatory demyelinating polyneuropathy (AIDP).
    Keywords:  Experimental autoimmune neuritis; Lactate; Macrophage glycolysis; PKM2; Th17 cells
    DOI:  https://doi.org/10.1016/j.intimp.2026.117162
  24. Cell Rep Med. 2026 Jul 23. pii: S2666-3791(26)00350-2. [Epub ahead of print] 102933
    Combination of exosome vaccines, lenvatinib, and anti-PD-1 eradicates tumor in autochthonous hepatocellular carcinoma mice.
    Bingfeng Zuo, Xuening Liu, Zheng Zhang, Zhenqiang Xu, Yanzhi Zhong, Yang Zhang, Qian Yang, Zezhen Yu, Kangjie Zhao, Yali Zhang, Yiqi Seow, HaiFang Yin.
      Unresectable hepatocellular carcinoma (HCC) demands more effective therapeutics to overcome its dismal prognosis. Dendritic cell (DC)-derived exosomes (DEXs) modified with CP05-anchored HCC-targeting peptide (P47-P), DC-recruiting and -activating high-mobility group nucleosome-binding protein 1 (HMGN1) (N1ND-N), and lymphotactin domains (XCL1-X) make DEXPNX. In situ antigen release by oral lenvatinib (LEN) with intravenous DEXPNX (DEXPNX/LEN) synergistically promotes intratumoral DC recruitment and activation. This enhances tumor neoantigen cross-presentation, de novo T cell responses, and durable immunological memory against rechallenge in orthotopic HCC mice. Furthermore, DEXPNX/LEN suppresses tumor growth and increases tumor-infiltrating CD8+ T cells in diethyl-nitrosamine (DENA)-induced and non-alcoholic steatohepatitis-associated HCC mice. Crucially, combining DEXPNX/LEN with anti-PD-1 eradicates established tumor and boosts intratumoral CD8+ effector T cell expansion in autochthonous HCC mice. Our study demonstrates a generalizable strategy to elicit personalized antitumor responses by leveraging DEX vaccines to activate tumoral DCs against LEN-released antigens, strengthened by anti-PD-1 blocking T cell exhaustion. This represents a clinically viable approach to improve HCC outcomes.
    Keywords:  anti-PD-1; exosome; hepatocellular carcinoma; lenvatinib; personalized immunotherapy
    DOI:  https://doi.org/10.1016/j.xcrm.2026.102933
  25. Pathol Res Pract. 2026 Jul 22. pii: S0344-0338(26)00282-7. [Epub ahead of print]286 156629
    Targeting the CD31 immunometabolic axis: Precision strategies for modulating T cell activation, migration, and autophagy.
    Xumeng Han, Feng Yang, Chaoyuan Huang, Zongzhen Meng, Aiping Lyu, Kenneth Cp Cheung.
      CD31 (PECAM-1) is broadly expressed on endothelial cells, platelets, and immune cells, where it helps set thresholds for immune activation and coordinates energy use. This Review synthesizes evidence that CD31 is a key regulator of immunometabolic pathways relevant to metabolic disease. We outline how CD31 restrains T-cell activation, guides T-cell migration, and adjusts metabolic reprogramming by balancing glycolysis with mitochondrial function to fine-tune effector responses. We also describe how CD31-dependent signaling at the vascular-immune interface shapes tissue inflammation in obesity, diabetes, and atherosclerosis. Both membrane CD31 and its soluble form (sCD31) show promise as biomarkers and as therapeutic entry points, and we summarize emerging strategies to modulate this pathway. We highlight outstanding challenges including pathway complexity, context dependence, and inter-individual variability that must be addressed to achieve clinical translation. By linking molecular mechanisms to disease phenotypes, this Review positions CD31 as a unifying node connecting vascular and immune control with metabolism, pointing to testable avenues for precision treatment of metabolic inflammation.
    Keywords:  CD31; ITIM; Immunometabolism; Inflammation; Metabolic diseases; PECAM-1
    DOI:  https://doi.org/10.1016/j.prp.2026.156629
  26. Nat Immunol. 2026 Jul 20.
    Endothelial cell-intrinsic NOD2 signaling regulates the intestinal immune response through the generation of effector and memory T cells.
    Boyan K Tsankov, Madison Denney, Jennifer S Y Ahn, Charles Carr, Nayanan Nathan, Derek K L Tsang, Giuliano Bayer, Lauren Baerg, Alexander Luchak, Tapas Mukherjee, Elaine Tam, Bana Samman, Jennifer L Gommerman, Stephen E Girardin, Dana J Philpott.
      Crohn's disease (CD) involves aberrant intestinal T cell immunity and genetic variants associated with disease development. Notably, mutations impairing NOD2 signaling represent the largest genetic risk factor for CD. Paradoxically, although NOD2 variants are associated with CD, its ligand, bacterial muramyl dipeptide, is a potent stimulator of immunity, long recognized as the minimal component required for the adjuvanticity of complete Freund's adjuvant. This paradox highlights a critical gap in our understanding of how NOD2 coordinates the innate-adaptive immune cross-talk required to maintain intestinal homeostasis. Here we show that NOD2 engagement by muramyl dipeptide drives T cell homing to the mesenteric lymph nodes during both homeostasis and infection. This recruitment promotes antigen-specific effector and memory T cell accumulation in the ileal lamina propria, a process essential for effective recall responses and clearance of secondary infection. Mechanistically, this process requires endothelial-intrinsic NOD2 expression, which drives a specialized transcriptional program for leukocyte recruitment.
    DOI:  https://doi.org/10.1038/s41590-026-02595-3
  27. Aging Cell. 2026 Aug;25(8): e70639
    Ammonia Metabolism in the Aging Liver: Emerging Mechanistic Insights.
    Heng Zhang, Guangyu Liang, Anding Liu.
      During aging, hepatic structural, metabolic, and regulatory impairments collectively contribute to the decline of hepatic and systemic function. As a core hepatic physiological process, ammonia metabolism is essential for maintaining systemic nitrogen homeostasis. However, how ammonia metabolism is altered during aging, and whether these changes contribute to hepatic and systemic decline, remain insufficiently understood. In this review, current evidence linking hepatic ammonia metabolism to liver aging is summarized. The major pathways of hepatic ammonia disposal, including the urea cycle and glutamine synthesis, are first outlined. Age-related changes in these pathways are then discussed, with emphasis on mitochondrial dysfunction, altered post-translational regulation, transcriptional and epigenetic remodeling, and disruption of metabolic zonation. Emerging evidence that ammonia functions not only as a nitrogen waste product but also as a bioactive stress signal is also reviewed. In this context, ammonia has been implicated in mitochondrial injury, senescence-associated signaling, proteostasis defects, and inflammatory and fibrogenic remodeling. The systemic consequences of ammonia dysregulation are further considered, particularly along the liver-brain, liver-muscle, and liver-gut axes. Finally, current and emerging therapeutic strategies are evaluated, including ammonia-lowering agents, senotherapeutics, and microbiota-directed approaches. Collectively, this review identify ammonia metabolism as an underappreciated but potentially axis for understanding liver aging, thereby providing a framework for future mechanistic and translational studies.
    Keywords:  aging; ammonia; liver
    DOI:  https://doi.org/10.1111/acel.70639
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