bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–06–15
23 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. Antigen-specific Th17 T cells offset the age-related decline in durable T cell immunity.
  2. The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.
  3. Targeting tumor metabolism to augment CD8+ T cell anti-tumor immunity.
  4. Pentose phosphate pathway inhibition metabolically reprograms CD8+ T cells and disrupts CNS autoimmunity.
  5. The mechanisms and clinical significance of CD8+ T cell exhaustion in anti-tumor immunity.
  6. Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.
  7. Nutrient-gene therapy as a strategy to enhance CAR T cell function and overcome barriers in the tumor microenvironment.
  8. Microbiome Metabolite-Incorporated Lipid Nanoparticles Augment CD8+ T Cell Memory Potential and Immunity for mRNA Cancer Vaccines.
  9. Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8+ T-cells during viral infection.
  10. Immunometabolism at the Crossroads of Infection: Mechanistic and Systems-Level Perspectives from Host and Pathogen.
  11. PGC1α-mediated mitochondrial fitness promotes Treg cell differentiation.
  12. IL-2 immunotherapy rescues irradiation-induced T cell exhaustion in mouse colon cancer.
  13. EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses.
  14. CXCL13 Expression Promotes CAR T Cell Antitumor Activity and Potentiates Response to PD-1 Blockade.
  15. Non-destructive, high-resolution T cell characterization and subtyping via deep-ultraviolet microscopy.
  16. Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer.
  17. Glucose-1-phosphate promotes compartmentalization of glycogen with the pentose phosphate pathway in CD8+ memory T cells.
  18. Noncanonical functions of T follicular helper cells.
  19. Author Correction: Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial.
  20. Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy.
  21. Modulating CD226 and PD-(L)1 pathways improves CMV-specific CD8＋T cell responses in the absence of IL-2.
  22. Emerging advancements in metabolic properties of macrophages within disease microenvironment for immune therapy.
  23. Precision Reprogramming-Restoring Function to Aged Cells.
  1. bioRxiv. 2025 Jun 06. pii: 2025.06.05.658069. [Epub ahead of print]
    Antigen-specific Th17 T cells offset the age-related decline in durable T cell immunity.
    Ines Sturmlechner, Abhinav Jain, Jingjing Jiang, Hirohisa Okuyama, Yunmei Mu, Maryam Own, Cornelia M Weyand, Jörg J Goronzy.
      Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells several years after vaccination in adults who had been vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine that confers durable protection only when given at young age, or with an adjuvanted VZV component vaccine that elicits effective, long-lasting immunity in older adults. CD8 + T cells were highly sensitive to age-related changes showing T cell subset shifts, loss in TCR diversity and reduced stem-like features while gaining NK-like signatures without evidence for cellular senescence or exhaustion. VZV-specific CD4 + T cells were largely resilient to age and maintained phenotypic and TCR diversity. Immunization of older adults with the adjuvanted VZV vaccine did not reverse age-associated defects in CD8 + T cells. Instead, it selectively improved the functionality of VZV-specific Th17 CD4 + T cells and prevented their acquisition of Treg features, likely as consequence of lipid metabolic pathways. Collectively, our data indicate that effective vaccination in older adults is supported by the generation of a durable, antigen-specific CD4 + Th17 population that resists mis-differentiation into Tregs and that compensates for age-related defects in CD8 + T cells.
    One sentence summary: Aging primarily impairs the CD8 + T cell VZV vaccine response, while effective VZV vaccination in older adults induces antigen-specific Th17 CD4 + T cells to compensate for aging defects.
    DOI:  https://doi.org/10.1101/2025.06.05.658069
  2. Cell Rep. 2025 Jun 05. pii: S2211-1247(25)00570-4. [Epub ahead of print]44(6): 115799
    The glycolytic reaction PGAM restrains Th17 pathogenicity and Th17-dependent autoimmunity.
    Chao Wang, Allon Wagner, Johannes Fessler, David DeTomaso, Sarah Zaghouani, Yulin Zhou, Kerry Pierce, Raymond A Sobel, Clary Clish, Nir Yosef, Vijay K Kuchroo.
      Glucose metabolism is a critical regulator of T cell function, largely thought to support their activation and effector differentiation. Here, we investigate how individual glycolytic reactions determine the pathogenicity of T helper 17 (Th17) cells using Compass, an algorithm we previously developed for inferring metabolic states from single-cell RNA sequencing. Surprisingly, Compass predicted that the metabolic shunt between 3-phosphoglycerate (3PG) and 2-phosphoglycerate (2PG) is inversely correlated with pathogenicity in Th17 cells. Indeed, perturbation of phosphoglycerate mutase (PGAM), the enzyme catalyzing 3PG to 2PG conversion, induces a pathogenic gene expression program by suppressing a gene module associated with the least pathogenic state of Th17 cells. Finally, PGAM inhibition in Th17 cells exacerbates neuroinflammation in the adoptive transfer model of experimental autoimmune encephalomyelitis, consistently with PGAM promoting the non-pathogenic phenotype of Th17 cells. Overall, our study identifies PGAM, contrary to other glycolytic enzymes, as a negative regulator of pathogenic Th17 cell differentiation.
    Keywords:  CP: Immunology; CP: Metabolism; EGCG; PGAM; PGM; T helper 17; central carbon metabolism; epigallocatechin-3-gallate; glycolysis; immune metabolism; immunometabolism; phosphoglycerate mutase
    DOI:  https://doi.org/10.1016/j.celrep.2025.115799
  3. J Pharm Anal. 2025 May;15(5): 101150
    Targeting tumor metabolism to augment CD8+ T cell anti-tumor immunity.
    Huan Liu, Wenyong Yang, Jingwen Jiang.
      CD8+ T cell-based immune-therapeutics, including immune checkpoint inhibitors and adoptive cell therapies (tumor-infiltrating lymphocytes (TILs), T cell receptor-engineered T cells (TCR-T), chimeric antigen receptor T cells (CAR-T)), have achieved significant successes and prolonged patient survival to varying extents and even achieved cure in some cases. However, immunotherapy resistance and tumor insusceptibility frequently occur, leading to treatment failure. Recent evidences have highlighted the ponderance of tumor cells metabolic reprogramming in establishing an immunosuppressive milieu through the secretion of harmful metabolites, immune-inhibitory cytokines, and alteration of gene expression, which suppress the activity of immune cells, particularly CD8+ T cells to evade immune surveillance. Therefore, targeting tumor cell metabolic adaptations to reshape the immune microenvironment holds promise as an immunomodulatory strategy to facilitate immunotherapy. Here, we summarize recent advances in the crosstalk between immunotherapy and tumor reprogramming, focusing on the regulatory mechanisms underlying tumor cell glucose metabolism, amino acid metabolism, and lipid metabolism in influencing CD8+ T cells to provide promising metabolic targets or combinational strategies for immunotherapy.
    Keywords:  CD8+ T cell; Immunotherapy; Metabolism reprogramming; TME; Tumor
    DOI:  https://doi.org/10.1016/j.jpha.2024.101150
  4. JCI Insight. 2025 Jun 10. pii: e184240. [Epub ahead of print]
    Pentose phosphate pathway inhibition metabolically reprograms CD8+ T cells and disrupts CNS autoimmunity.
    Ethan M Grund, Benjamin Ds Clarkson, Susanna Pucci, Maria S Westphal, Carolina Muniz Partida, Sara A Muhammad, Charles L Howe.
      Multiple sclerosis is characterized by CNS infiltration of auto-reactive immune cells that drive both acute inflammatory demyelination and chronic progressive axonal and neuronal injury. Expanding evidence implicates CD8+ anti-neural T cells in the irreversible neurodegeneration that underlies progression in multiple sclerosis, yet therapies specifically targeting this cell population are limited. CD8+ T cells from patients with MS exhibit increased engagement of the pentose phosphate pathway. Pharmacologic inhibition of the pentose phosphate pathway reduced glycolysis, glucose uptake, NADPH production, ATP production, proliferation, and proinflammatory cytokine secretion in CD8+ T cells activated by ligation of CD3 and CD28. Pentose phosphate pathway inhibition also prevented CD8+ T cell-mediated antigen-specific neuronal injury in vitro and in both an adoptive transfer-based cuprizone model of demyelination and in mice with experimental autoimmune encephalomyelitis. Notably, transcriptional profiling of CNS-infiltrating CD8+ T cells in patients with MS indicated increased pentose phosphate pathway engagement, suggesting that this pathway is involved in CD8+ T cell-mediated injury of axons and neurons in the demyelinated CNS. Inhibiting the pentose phosphate pathway disrupts CD8+ T cell metabolic reprogramming and effector functions, suggesting that such inhibition may serve as a therapeutic strategy to prevent neurodegeneration in patients with progressive MS.
    Keywords:  Autoimmune diseases; Autoimmunity; Glucose metabolism; Immunology; Multiple sclerosis; Neuroscience
    DOI:  https://doi.org/10.1172/jci.insight.184240
  5. Cancer Biol Med. 2025 Jun 10. pii: j.issn.2095-3941.2024.0628. [Epub ahead of print]
    The mechanisms and clinical significance of CD8+ T cell exhaustion in anti-tumor immunity.
    Tao Zhong, Shuo Sun, Mingsheng Zhao, Bin Zhang, Huabao Xiong.
      CD8+ T cell exhaustion, a critical challenge in the immune response to cancer, is characterized by a profound decline in the functionality of effector CD8+ T cells. This state of exhaustion is accompanied by the upregulation of various inhibitory receptors and significant shifts in both transcriptional and epigenetic profiles, thus ultimately leading to inadequate tumor control. Therapeutic strategies aimed at reversing CD8+ T cell exhaustion have the potential to rejuvenate immune responses and enhance treatment efficacy. This review compiles current knowledge regarding the molecular mechanisms underlying CD8+ T cell exhaustion, including the roles of immune checkpoint molecules, the tumor microenvironment, metabolic reprogramming, transcription factors, and epigenetic modifications. Emerging therapeutic approaches designed to combat CD8+ T cell exhaustion are evaluated, with emphasis on the modulation of immune checkpoints; targeting of metabolic and transcriptional changes; and exploration of other innovative strategies, such as epigenetic editing and engineered CAR-T cells. Importantly, we expand the exhaustion concept to immune cells beyond CD8+ T cells, such as CD4+ T cells, natural killer cells, and myeloid populations, thereby highlighting the broader implications of systemic immunosuppression in the cancer context. Finally, we propose avenues for future research aimed at further elucidating the factors and molecular mechanisms associated with CD8+ T cell exhaustion, thereby underscoring the critical need for strategies aimed at reversing this state to improve outcomes in cancer immunotherapy.
    Keywords:  CD8+ T cell exhaustion; anti-tumor immunity; cancer immunotherapy; immune checkpoint; immune checkpoint inhibitors
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2024.0628
  6. Cell. 2025 Jun 03. pii: S0092-8674(25)00563-X. [Epub ahead of print]
    Microbiota-derived inosine programs protective CD8+ T cell responses against influenza in newborns.
    Joseph Stevens, Erica Culberson, Jeremy Kinder, Alicia Ramiriqui, Jerilyn Gray, Madeline Bonfield, Tzu-Yu Shao, Faris Al Gharaibeh, Laura Peterson, Shelby Steinmeyer, Emily M Eshleman, Shikha Negi, William Zacharias, Gloria Pryhuber, Oindrila Paul, Shaon Sengupta, Theresa Alenghat, Sing Sing Way, Hitesh Deshmukh.
      Early-life susceptibility to respiratory viral infections remains a major public health concern, yet the underlying mechanisms are poorly understood. We demonstrate that antibiotic-induced dysbiosis impairs influenza-specific CD8+ T cell immunity in infant mice and humans through the disruption of nuclear factor interleukin 3 (NFIL3)-dependent T cell programming. Mechanistically, we show that dysbiosis reduces intestinal and circulating inosine levels, disrupting NFIL3's epigenetic regulation of T cell factor 1 (TCF1) expression. This leads to intrinsic defects in CD8+ T cell proliferation and differentiation, diminished effector responses, and impaired formation of tissue-resident memory cells. Bifidobacterium colonization restores intestinal and pulmonary inosine levels, establishing a specific pathway of gut-lung metabolic communication. Notably, inosine supplementation rescues NFIL3-dependent regulation of TCF1, enhancing CD8+ T cell responses and protection against influenza infection in dysbiotic infants. Our findings reveal how early-life microbial communities shape antiviral immunity and identify inosine as a therapeutic target for enhancing respiratory defenses in infants.
    Keywords:  T cell responses; immunology; infants; influenza; inosine; microbiota
    DOI:  https://doi.org/10.1016/j.cell.2025.05.013
  7. J Transl Med. 2025 Jun 06. 23(1): 633
    Nutrient-gene therapy as a strategy to enhance CAR T cell function and overcome barriers in the tumor microenvironment.
    Brandon Park, Joshua Kim, David J Baylink, Christopher Hino, Cedric Kwon, Victoria Tran, Jeffrey Xiao, Huynh Cao, Scott Lee, Laren Tan, Andrew Chang, Luis Saca, Michael Matus, Pamela Lobo Moreno, Amy Schill-Depew, Hisham Abdel-Azim, Hamid Mirshahidi, Yi Xu.
      Cancer immunotherapy is transforming the treatment landscape of both hematological and solid cancers. Although T-cell-based adoptive cell transfer (ACT) therapies have demonstrated initial success, several recurrent obstacles limit their long-term anti-tumor efficacy, including: (1) lack of antigen specificity; (2) poor long-term survival of transplanted T cells in vivo; and (3) a hostile tumor microenvironment (TME). While numerous approaches have been explored to enhance the antigen specificity of Chimeric Antigen Receptor (CAR) T-cell therapies, the field still lacks an effective strategy to optimize the long-term retention and in vivo expansion of engrafted T cells within the TME-a critical factor for the durable efficacy of T-cell-based immunotherapies for both blood and solid cancers. Here, we hypothesize that the success of CAR T-cell therapy can be enhanced by targeting donor T cells' ability to compete with cancer cells for key nutrients, thereby overcoming T-cell exhaustion and sustaining durable anti-tumor function in the TME. To explore this hypothesis, we first provide a comprehensively review of the current understanding of the metabolic interactions (e.g., glucose metabolism) between T cells and tumor cells. To address the challenges, we propose an innovative strategy: utilizing nutrient gene therapy (genetic overexpression of glucose transporter 1, GLUT1) to fortify the metabolic competency of adoptive CAR T-cells, deprive tumors of critical metabolites and ATP, and disrupt the TME. Altogether, our proposed approach combining precision medicine (adoptive CAR T-cell therapy) with tumor metabolism-targeting strategies offers a promising and cost-effective solution to enhance the efficacy and durability of ACT therapies, ultimately improving outcomes for cancer patients.
    Keywords:  Adoptive cell therapy; CAR T; Cancer immunotherapy; GLUT1; Gene therapy; Glucose; Metabolite; Nutrient; TME; Warburg effect
    DOI:  https://doi.org/10.1186/s12967-025-06606-z
  8. ACS Biomater Sci Eng. 2025 Jun 09.
    Microbiome Metabolite-Incorporated Lipid Nanoparticles Augment CD8+ T Cell Memory Potential and Immunity for mRNA Cancer Vaccines.
    Seok-Beom Yong, Minki Ha, Sungchan Cho.
      Recently, mRNA/lipid nanoparticle (LNP)-based vaccines have been successfully applied to prevent infectious diseases, and several types of neoantigen-encoding mRNA cancer vaccines are currently under clinical trials. While mRNA vaccines effectively induce adaptive immune responses to antigens, mRNA vaccine-induced immunity is shortly maintained, and the longevity of the immune memory, especially improving the CD8+ T cell memory potential, could be even more important. Previously, microbiome metabolites have shown T cell memory potential-augmenting effects via regulating the immunometabolism. Herein, we develop microbiome metabolite-incorporated LNPs (mmi-LNPs) and evaluate their potential to enhance T cell memory responses following mRNA vaccination. In various ionizable LNP formulations, mmi-LNPs elicited more stem cell-like memory T cells (T-SCMs) and augmented central and effector memory T cell responses, which indicates the general applicability of mmi-LNPs. Notably, butyrate-incorporated mmi-LNP exhibited the strongest effects. In conclusion, we suggest microbiome metabolite-incorporated LNP as a next-generation delivery vehicle for mRNA vaccines.
    Keywords:  CD8+ T cell memory potential-improving LNPs; mRNA cancer vaccine; microbiome metabolite-incorporated LNP
    DOI:  https://doi.org/10.1021/acsbiomaterials.5c00738
  9. EMBO J. 2025 Jun 10.
    Transcription factor IRF-5 regulates lipid metabolism and mitochondrial function in murine CD8+ T-cells during viral infection.
    Linh Thuy Mai, Sharada Swaminathan, Trieu Hai Nguyen, Etienne Collette, Tania Charpentier, Liseth Carmona-Pérez, Hamza Loucif, Alain Lamarre, Krista M Heinonen, David Langlais, Jörg H Fritz, Simona Stäger.
      Exhaustion of CD8+ T-cells leads to their reduced immune functionality and is controlled by numerous transcription factors. Here we show that the transcription factor IRF-5 helps to limit functional exhaustion of murine CD8+ T-cells during the chronic stage of LCMV (CL13) viral infection. Our results suggest that T-cell inhibitory receptors and transcription factor TOX, which are implicated in dampening T-cell activation and promoting exhaustion, are upregulated in infected IRF-5-deficient CD8+ T-cells. In addition, these cells display a reduced capacity to produce cytokines and lower survival rates than wild-type cells. Our findings indicate that these effects are mediated by defective lipid metabolism, increased lipid peroxidation, enhanced mitochondrial ROS production, and reduced levels of oxidative phosphorylation in the absence of IRF-5. These results identify IRF-5 as an important regulator of lipid metabolism and mitochondrial function that protects CD8+ T-cells from functional exhaustion during the chronic stage of viral infection.
    Keywords:  CD8 T Cells; Cell Exhaustion; IRF-5; Lipid Metabolism; Mitochondria
    DOI:  https://doi.org/10.1038/s44318-025-00485-2
  10. ArXiv. 2025 Jun 02. pii: arXiv:2506.02236v1. [Epub ahead of print]
    Immunometabolism at the Crossroads of Infection: Mechanistic and Systems-Level Perspectives from Host and Pathogen.
    Sunayana Malla, Nabia Shahreen, Rajib Saha.
      The emerging field of immunometabolism has underscored the central role of metabolic pathways in orchestrating immune cell function. Far from being passive background processes, metabolic activities actively regulate key immune responses. Fundamental pathways such as glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation critically shape the behavior of immune cells, influencing macrophage polarization, T cell activation, and dendritic cell function. In this review, we synthesize recent advances in immunometabolism, with a focus on the metabolic mechanisms that govern the responses of both innate and adaptive immune cells to bacterial, viral, and fungal pathogens. Drawing on experimental, computational, and integrative methodologies, we highlight how metabolic reprogramming contributes to host defense in response to infection. These findings reveal new opportunities for therapeutic intervention, suggesting that modulation of metabolic pathways could enhance immune function and improve pathogen clearance.
  11. Cell Immunol. 2025 May 30. pii: S0008-8749(25)00071-1. [Epub ahead of print]414 104985
    PGC1α-mediated mitochondrial fitness promotes Treg cell differentiation.
    Luis Eduardo Alves Damasceno, Gabriel Alberto de Carvalho Barbosa, Tim Sparwasser, Thiago Mattar Cunha, Fernando Queiroz Cunha, José Carlos Alves-Filho.
      Regulatory T (Treg) cells play a critical role in the maintenance of immune tolerance to self-antigens and suppression of excessive immune responses. They employ a distinct metabolic profile from other CD4 T cell subsets to support their differentiation and suppressive function, which is characterized by enhanced mitochondrial metabolism. Although PGC1α is considered a master regulator of mitochondrial biogenesis and function, its role in Treg cell differentiation remains unclear. Herein, we demonstrated that PGC1α is highly expressed in Treg cells compared to other CD4 T cell populations. Using a pharmacological approach, we found that its transcriptional activation in iTreg cells enhanced mitochondrial fitness, characterized by increased expression of mitochondrial genes, mitochondrial mass, and metabolic activity. Moreover, PGC1α activation enhanced both mouse and human iTreg cell differentiation, while its inhibition reduced this process. Therefore, our findings shed light on the potential role of PGC1α as a pharmacological target when manipulating Treg cells as a therapeutic strategy.
    Keywords:  Mitochondria; PGC1α; T(reg) cell
    DOI:  https://doi.org/10.1016/j.cellimm.2025.104985
  12. iScience. 2025 Jun 20. 28(6): 112639
    IL-2 immunotherapy rescues irradiation-induced T cell exhaustion in mouse colon cancer.
    Carmen S M Yong, Irma Telarovic, Lisa Gregor, Miro E Raeber, Martin Pruschy, Onur Boyman.
      Radiotherapy (RT) can stimulate anti-cancer T cell responses, and cytokines, notably interleukin-2 (IL-2), are necessary for optimal T cell function and memory. However, timing and IL-2 receptor (IL-2R) bias of IL-2 signals are ill-defined. Using image-guided RT in a mouse colon cancer model, we observed single high-dose (20 Gy) RT transiently upregulated IL-2Rα (CD25) on effector CD8+ T cells, facilitating the use of CD25-biased IL-2 immunotherapy. Timed administration of CD25-biased IL-2 treatment after RT favored intratumoral expansion of CD8+ T cells over regulatory T cells, which resulted in comparable anti-tumor effects as with RT plus IL-2Rβ (CD122)-biased IL-2 immunotherapy. Moreover, intratumoral CD8+ T cells of animals receiving combined IL-2R-biased IL-2 and RT showed reduced markers of exhaustion. These combination treatments affected both primary irradiated and distant non-irradiated tumors and achieved durable responses. We demonstrate that timed IL-2R subunit-biased IL-2 immunotherapy synergizes with single high-dose RT to achieve potent anti-cancer immunity.
    Keywords:  Cancer; Immunology; Microenvironment
    DOI:  https://doi.org/10.1016/j.isci.2025.112639
  13. Cell Chem Biol. 2025 Jun 03. pii: S2451-9456(25)00168-0. [Epub ahead of print]
    EGR2 O-GlcNAcylation orchestrates the development of protumoral macrophages to limit CD8+ T cell antitumor responses.
    Yuchen Zhang, Hongpeng Li, Yi Hao, Jiaqi Chen, Xing Chen, Hang Yin.
      Tumor associated macrophages (TAMs) exhibit a high capacity to take up glucose. However, how metabolic cues derived from glucose rewire TAMs remains unclear. Here, we report that glucose metabolism-driven protein O-GlcNAcylation increases in TAMs and shapes the differentiation and protumoral function of TAMs. Deficiency of O-GlcNAc transferase (OGT) in TAMs restricted tumor growth by reducing the proportion of C1QC+ F4/80+ TREM2+ MerTK+ TAMs as well as Trem2 expression, which in turn preserved the cytotoxic function of effector CD8+ T cells while exhibiting reduced features of exhaustion. Mechanistically, O-GlcNAc targeted the macrophage-specific transcription factor EGR2 to promote its transcriptional activity. Transcriptional profiling revealed that OGT increased EGR2-related motifs accessibility in TAMs. O-GlcNAcylation of EGR2 at serine 299 enhanced its binding to myeloid cell differentiation-associated genes, including Trem2, thus facilitating the protumoral function of TAMs in GM-CSF-sufficient tumor. Overall, our work defines a tumor-specific reprogramming of protumoral TAMs via O-GlcNAc-modified EGR2 transcriptional regulation.
    Keywords:  CD8(+) T cells; EGR2; GM-CSF; TREM2; anti-tumor immunity; glucose metabolism; post-translational modification; protein O-GlcNAcylation; tumor associated macrophages; tumor microenvironment
    DOI:  https://doi.org/10.1016/j.chembiol.2025.05.007
  14. Adv Sci (Weinh). 2025 Jun 10. e08095
    CXCL13 Expression Promotes CAR T Cell Antitumor Activity and Potentiates Response to PD-1 Blockade.
    Yang Zhou, Wenli Zhao, Yihan Zhu, Hongyan Liu, Yicheng Sun, Zhengrong Gong, Xuanyi Li, Ziying Liu, Kang Wen, Yicheng Wang, Jie Ren, Ruipei Xiao, Ling Jiang, Yanfeng Hu, Enguang Bi, Xiaoyong Zhang.
      Immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cell therapies have revolutionized cancer immunotherapy, offering significant benefits across various cancers. However, challenges remain, particularly in solid tumors where immunosuppressive tumor microenvironments and T cell exhaustion limit effectiveness. Combining ICB with CAR T cell therapy has shown potential but requires further optimization for effective synergy. Here, the bioinformatic analysis identified that CXCL13 expression is highly elevated in T cells from patients who respond to ICB, indicating its possible role in enhancing T cell antitumor responses. Mouse CAR T cells are engineered to overexpress CXCL13 and observed that these cells displayed reduced exhaustion, increased central memory phenotype, and improved mitochondrial function and proliferation in an AKT-mTOR dependent manner. CXCL13-overexpressing CAR T cells show significantly increased antitumor activity in vivo, particularly when combined with PD-1 inhibition, promoting the expansion and persistence of early exhausted CD8+ CAR T cells. CXCL13 also conferred similar in vitro phenotypic enhancements in human CAR T cells as observed in murine cells. These results indicate that CXCL13 expression improves CAR T cell function and responsiveness to ICB, offering a promising and translationally relevant strategy to optimize CAR T cell therapy for solid tumors in clinical settings.
    Keywords:  CAR T cells; CXCL13; immune checkpoint blockade
    DOI:  https://doi.org/10.1002/advs.202508095
  15. bioRxiv. 2025 May 26. pii: 2025.05.20.655120. [Epub ahead of print]
    Non-destructive, high-resolution T cell characterization and subtyping via deep-ultraviolet microscopy.
    Viswanath Gorti, Caroline E Serafini, Aaron D Silva Trenkle, Kaitlyn McCubbins, Isaac LeCompte, Gabriel A Kwong, Francisco E Robles.
      T cell characterization is critical for understanding immune function, monitoring disease progression, and optimizing cell-based therapies. Current technologies to characterize T cells, such as flow cytometry, require fluorescent labeling and typically are destructive endpoint measurements. Non-destructive, label-free imaging methods have been proposed, but face limitations with throughput, specificity, and system complexity. Here we demonstrate deep-ultraviolet (UV) microscopy as a label-free, non-destructive, fast and simple imaging approach for assessing T cell viability, activation state, and subtype with high accuracy. Using static deep-UV images, we characterize T cell viability and activation state, demonstrating excellent agreement with flow cytometry measurements. We further apply dynamic deep-UV imaging to quantify intracellular activity, enabling fast and accurate subtyping of CD4 + and CD8 + T cells. These results corroborate recent studies on metabolic activity differences between these subtypes, but now with deep-UV microscopy they are enabled by a non-destructive, fast, low-cost and simple approach. Together, our results demonstrate deep-UV microscopy as a powerful tool for high-throughput immune cell characterization, with broad applications in immunology re-search, immune monitoring, and development of emerging cell-based therapies.
    DOI:  https://doi.org/10.1101/2025.05.20.655120
  16. bioRxiv. 2025 May 27. pii: 2025.05.22.655365. [Epub ahead of print]
    Disabling PSGL-1 abrogates immune suppression and resistance to PD-1 blockade in pancreatic cancer.
    Jennifer L Hope, Yijuan Zhang, Hannah A F Hetrick, Evelyn S Sanchez-Hernandez, Beatrice Silvestri, Brianna J Smith, Sanmati H Nakil, Sreeja Roy, Michelle Lin, Ashley B Palete, Swetha Maganti, Lily Ling, Dennis C Otero, Katelyn T Byrne, Gabriele Romano, Yu Xin Wang, Cosimo Commisso, Linda M Bradley.
      Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer for which there is a critical need to identify novel therapeutic targets. Herein we define PSGL-1 as a checkpoint inhibitor using a syngeneic orthotopic model of PDAC. As with PDAC patients, CD8 + T cells within murine PDAC tumors expressed high levels of PSGL-1. PSGL-1 -/- mice displayed striking T cell-dependent control of primary tumors and lung metastases. Extensive spatial remodeling within PDAC tumors occurred in PSGL-1 -/- mice with a dramatic loss of proliferating tumor cells and an increase in CD8 + T cell engagement of antigen-presenting cells. The prominent CD8 + T cell infiltrates included subsets of pre-exhausted T cells retaining hallmarks of stemness and multifunctional effector capacity. These changes enabled a near complete response of PDAC to therapeutic PD-1 blockade. Our findings identify PSGL-1 as a key regulator of anti-tumor immunity in PDAC, highlighting its potential as a therapeutic target to limit CD8 + T cell exhaustion and enhance immunotherapy response.
    Summary: Hope et al describe a pivotal function of PSGL-1 in CD8 + T cell responses to pancreatic ductal adenocarcinoma. Genetic deletion of PSGL-1 elicits tumor control by increasing T cell infiltration and maintaining functional subsets, thereby promoting sensitivity to PD-1 blockade.
    DOI:  https://doi.org/10.1101/2025.05.22.655365
  17. Mol Cell. 2025 Jun 03. pii: S1097-2765(25)00458-7. [Epub ahead of print]
    Glucose-1-phosphate promotes compartmentalization of glycogen with the pentose phosphate pathway in CD8+ memory T cells.
    Yabo Zhou, Chaoying Zhang, Lina He, Youli Kang, Dianheng Wang, Shujing Wang, Zheng Ling, Jie Chen, Nannan Zhou, Li Zhou, Zhenfeng Wang, Chaoqi Zhang, Ke Tang, Huafeng Zhang, Jingwei Ma, Bo Qin, Sheng Cui, Jiadi Lv, Bo Huang.
      Glucose-6-phosphate (G6P) is a key metabolic molecule that regulates reactive oxygen species (ROS) homeostasis by initiating the pentose phosphate pathway (PPP) to generate nicotinamide adenine dinucleotide phosohate (NADPH) that converts hydrogen peroxide (H2O2) to water by providing hydrogen. While both glucose phosphorylation and glycogenolysis result in G6P production, here we show that G6P derived from glycogenolysis, rather than glucose phosphorylation, flows to PPP for ROS clearance in CD8+ memory T (Tm) cells and inflammatory macrophages. Mechanistically, glycogenolysis-produced glucose-1-phosphate (G1P) allosterically induces G6P dehydrogenase (G6PD) binding to glycogen, which together undergo liquid-liquid phase separation (LLPS) and recruit PPP enzymes, resulting in a compartmentalized reaction cascade. Based on mechanistic elucidation, we demonstrated that G1P can act as an antitumor immunotherapeutic agent by modulating memory fitness and maintenance of tumor-reactive CD8+ T cells in mice. These findings revealed an unusual function of glycogen metabolism, which is of paramount importance in the regulation of PPP and redox homeostasis in cells.
    Keywords:  CD8(+) T(m); G1P; G6PD; LLPS; PPP; ROS; compartmentalization; glycogen
    DOI:  https://doi.org/10.1016/j.molcel.2025.05.019
  18. Sci Immunol. 2025 Jun 13. 10(108): eadr1052
    Noncanonical functions of T follicular helper cells.
    Shivangi Dave, André Ballesteros-Tato.
      T follicular helper cells (TFH cells) are essential for germinal center (GC) formation and maintenance. However, recent insights reveal that TFH cells play additional immune regulatory roles beyond their traditional B cell helper function. Here, we review the functional and anatomical diversity of TFH cells and their unconventional roles in modulating immune responses during infection, vaccination, allergy, and tolerance. These functions include their stem-like memory T cell properties and their role as reservoirs for effector T cell (Teff cell) precursors. We also summarize the contributions of "ex-TFH cells" to immune homeostasis and the functions of diverse subsets of cytokine-producing TFH cells in aiding CD8+ T cells and regulating critical B cell fate decisions. In summary, this Review underscores the multifaceted contributions of TFH cells to immune regulation, extending beyond their traditional B cell helper roles.
    DOI:  https://doi.org/10.1126/sciimmunol.adr1052
  19. Nat Med. 2025 Jun 11.
    Author Correction: Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial.
    Stephen J Bagley, Arati S Desai, Joseph A Fraietta, Dana Silverbush, Daniel Chafamo, Nelson F Freeburg, Gayathri Konanur Gopikrishna, Andrew J Rech, Ali Nabavizadeh, Linda J Bagley, Jungmin Park, Danuta Jarocha, Rene Martins, Nicolas Sarmiento, Eileen Maloney, Lester Lledo, Carly Stein, Amy Marshall, Rachel M Leskowitz, Julie K Jadlowsky, Shane Mackey, Shannon Christensen, Bike Su Oner, Gabriela Plesa, Andrea Brennan, Vanessa Gonzalez, Fang Chen, David Barrett, Robert Colbourn, MacLean P Nasrallah, Zissimos Mourelatos, Wei-Ting Hwang, Cecile Alanio, Donald L Siegel, Carl H June, Elizabeth O Hexner, Zev A Binder, Donald M O'Rourke.
      
    DOI:  https://doi.org/10.1038/s41591-025-03824-2
  20. Cancer Cell. 2025 Jun 04. pii: S1535-6108(25)00215-6. [Epub ahead of print]
    Mutant KRAS peptide targeted CAR-T cells engineered for cancer therapy.
    Alexander Benton, Jiageng Liu, Mathilde A Poussin, Andrea Lang Goldgewicht, Madhara Udawela, Adham S Bear, Nils Wellhausen, Beatriz M Carreno, Pete M Smith, Matthew D Beasley, Ben R Kiefel, Daniel J Powell.
      Despite the success of chimeric antigen receptor (CAR)-T cell therapies in hematological malignancies, clinical success against solid tumors is limited due to low therapeutic efficacy or dose-limiting toxicity. Developing therapies that trigger potent, yet manageable, immune responses capable of eliminating highly heterogeneous and immunosuppressive tumor cell populations remains a key challenge. Here, we harness multiple genetic approaches to develop a CAR-T cell therapy targeting tumors. First, we screen binders targeting oncogenic KRAS G12V mutations presented by peptide-MHC complexes. Subsequently, we incorporate these neoantigen binders into CAR-T cells (mKRAS NeoCARs) and demonstrate their efficacy in xenograft models of metastatic lung, pancreatic, and renal cell cancer. Finally, we enhance the in vivo efficacy and safety profile of mKRAS NeoCARs via inducible secretion of IL-12 and T cell receptor deletion. Together, these screening and engineering processes provide a modular platform for expanding the therapeutic index of cellular immunotherapies that target cancer.
    Keywords:  CART; CRISPR; IL-12; KRAS; T cell; armored CAR; cellular immunotherapy; neo-antigen; peptide; solid tumors; therapeutic index
    DOI:  https://doi.org/10.1016/j.ccell.2025.05.006
  21. BMB Rep. 2025 Jun 11. pii: 6479. [Epub ahead of print]
    Modulating CD226 and PD-(L)1 pathways improves CMV-specific CD8＋T cell responses in the absence of IL-2.
    Hye-In Sim, Yunju Jo, Hyejin Ahn, Juyeon Hong, Hye-Bin Kim, Bohwan Yun, Haeun Son, Yeonjun Jeong, Jibaek Kim, Chan-Sik Park, Yoon Park, Hyung-Seung Jin.
      Glioblastoma (GBM) frequently expresses cytomegalovirus (CMV) antigens, making CMV-specific CD8＋T cells attractive candidates for adoptive immunotherapy due to their longevity and inherent tumor reactivity. However, these T cells encounter significant immunosuppressive challenges within the GBM microenvironment, including cytokine scarcity and checkpointmediated inhibition, which limit their proliferation and function. Here, we assessed strategies to overcome these limitations by modulating immune checkpoint pathways. Antigen stimulation combined with IL-2 robustly expanded high-avidity (tetramer-high) CMV-specific T cells with significant enrichment of CD62L＋ central memory (TCM) cells. In contrast, antigen stimulation alone modestly expanded tetramer-high cells with limited TCM enrichment. PD-L1 blockade in the absence of IL-2 favored expansion of tetramer-high CMV-specific CD8＋T cells, preserved CD62L expression, and enhanced CD226 expression. Furthermore, combining anti-PD-L1 blockade with an anti-CD226 agonist markedly enhanced proliferation, IFN-γ production, and TCM enrichment in both tetramer-high and tetramer-low populations, reaching levels comparable to IL-2-supported conditions. Together, these findings highlight that simultaneous modulation of PD-L1 and CD226 pathways can restore CMV-specific T cell function, offering a promising strategy to boost TCR-T efficacy in cytokine-deprived environments.
  22. J Innate Immun. 2025 Jun 11. 1-27
    Emerging advancements in metabolic properties of macrophages within disease microenvironment for immune therapy.
    Feng Zhao, Zhongyu Yue, Lijiaqi Zhang, Yujie Qi, Yunting Sun, Shuling Wang, Qingchang Tian.
       BACKGROUND: As sentinel cells of innate immunity, macrophages exhibit microenvironment-driven functional plasticity critical for immune regulation and tissue homeostasis, yet maladaptive metabolic reprogramming-induced polarization dysregulation exacerbates disease progression by manifesting immune dysfunction Summary: This review systematically deciphers the metabolic signatures governing macrophage polarization - spanning amino acid metabolism, glycolytic flux, lipid dynamics, and iron homeostasis - while dissecting how pathological microenvironments (encompassing tumor niches, atherosclerotic plaques, and obese adipose tissue) co-opt these pathways to drive pathogenesis. Crucially, this analysis demonstrates that cellular metabolism dictates macrophage phenotypic/functional states across disease contexts, with comprehensive decoding of their metabolic networks emerging as imperative for developing next-generation immunotherapies.
    KEY MESSAGES: Therapeutically, pathogenic polarization may be reversed through strategic interventions targeting metabolite-sensing receptors, pharmacologically blocking metabolic checkpoints, and reprogramming core metabolic modalities to restore immunoregulatory competence.
    DOI:  https://doi.org/10.1159/000546476
  23. Cell Reprogram. 2025 Jun 09.
    Precision Reprogramming-Restoring Function to Aged Cells.
    Arjun Jain, Yuuki Hosokawa, Kevin Joseph.
      Sahu et al. (2024) demonstrate that targeted partial reprogramming with Oct4, Sox2, and Klf4 (OSK) delivered via adeno-associated virus (AAV) to Cdkn2a-positive cells rejuvenates senescent cells while maintaining cellular identity. In a progeroid and naturally aged mouse model, a single AAV injection improved lifespan, reduced inflammation, restored tissue integrity, and enhanced wound healing. Complementary results in human fibroblasts confirmed Cdkn2a-driven OSK expression attenuated inflammation-associated genes during replicative senescence and treatments inducing DNA damage. These encouraging results highlight its potential as a safer alternative to systemic senolytic therapies for age-associated disorders.
    Keywords:  Hutchinson-Gilford progeria syndrome; aging; partial reprogramming; senescent cells
    DOI:  https://doi.org/10.1089/cell.2025.0018
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