bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–07–20
twenty papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research
  1. MEK-dependent bioenergetic demand drives terminal CD8 + T cell exhaustion.
  2. Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
  3. Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
  4. Accumulation of SA-βGal-High Cells in Human Naïve T Cell Compartments Reveals a Stress-Adapted, Senescent-Like State.
  5. Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.
  6. ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality.
  7. CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients.
  8. Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging.
  9. Intratumoral amino acid insufficiency limits CD8 + T-cell effector function.
  10. Regenerative Immunotherapy for Cancer: Transcription Factor Reprogramming of Tumor-Specific T Cells.
  11. Targeting the hallmarks of aging: mechanisms and therapeutic opportunities.
  12. CD8 + T Cells in Gastrointestinal Cancer: a Perspective on Targeting MicroRNA.
  13. Nicotinamide riboside treatment enhances stress sensitivity and modulates hematological dynamics in aged mice.
  14. CD38 expression by neonatal human naïve CD4 + T cells shapes their distinct metabolic state and tolerogenic potential.
  15. Activating the CXCR3/CXCL10 pathway overrides tumor immune suppression by enhancing immune trafficking and effector cell priming in head and neck squamous cell carcinoma.
  16. T lymphocyte-specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4+ T cells and impairs antitumor response.
  17. Disruption of cell-intrinsic PCSK9 enhances the antitumor efficacy of CD8+ T cells.
  18. Cancer progression through the lens of age-induced metabolic reprogramming.
  19. Small molecule modulators of TOX protein re-invigorate T cell activity.
  20. IL-4 impairs the formation of skin-resident memory CD8+ T cells.
  1. bioRxiv. 2025 May 05. pii: 2025.04.30.651453. [Epub ahead of print]
    MEK-dependent bioenergetic demand drives terminal CD8 + T cell exhaustion.
    Tanmana Mitra, Jahan Rahman, Madeline Hwee, Ruben Jose Jesus Faustino Ramos, Hui Liu, Travis Hartman, Justin Cross, Miguel de Jesus, Morgan Huse, Valerie Longo, Pat Zanzonico, Santosha A Vardhana.
      Loss of mitochondrial function contributes to CD8 + T cell dysfunction during persistent antigen encounter. How chronic antigen leads to this metabolic dysfunction remains unclear. Here, we show that TCR-dependent mitochondrial NADH accumulation drives production of ROS, ultimately leading to mitochondrial dysfunction. Among TCR-dependent proximal signaling components, MEK inhibition uniquely reduced nutrient uptake and mitochondrial NADH accumulation while increasing proliferation. As a result, MEK inhibition during chronic TCR stimulation reduced terminal T cell exhaustion. Mechanistically, we found that chronic MEK activation in T cells drove ATP demand by increasing global protein synthesis rates in vitro and in vivo . MEK inhibition reversed chronic TCR stimulation-driven increases in RNA polymerase II CTD phosphorylation, reducing transcription rates at effector- and terminal-exhaustion associated genes while maintaining transcription of memory-associated genes. These findings establish MEK-dependent metabolic demand as a driver of T cell exhaustion and elucidate the role of MEK inhibition in enhancing immunotherapy efficacy.
    DOI:  https://doi.org/10.1101/2025.04.30.651453
  2. Nat Immunol. 2025 Jul 16.
    Mitochondrial respiration is necessary for CD8+ T cell proliferation and cell fate.
    Elizabeth M Steinert, Beatriz Furtado Bruza, Veronika D Danchine, Rogan A Grant, Karthik Vasan, Arjun Kharel, Yuqi Zhang, Weiguo Cui, Marten Szibor, Samuel E Weinberg, Navdeep S Chandel.
      Mitochondrial electron transport chain (ETC) function is linked to the generation of ATP, signaling molecules including reactive oxygen species (ROS), pyrimidines and tricarboxylic acid cycle metabolites1. Mitochondrial electron transport is required for T cell proliferation2-4. However, which mitochondrial ETC functions are necessary for each dynamic state of CD8+ T cell responses is unknown. Here we report that impairing mitochondrial complex III function, which diminishes respiration, proton pumping linked to ATP production and superoxide production, decreases peripheral naive numbers, antigen-induced CD8+ T cell proliferation and memory formation. Acute stimulation of mitochondrial complex III-deficient CD8+ T cells induced an exhausted-like phenotype. Expression of Ciona intestinalis alternative oxidase (AOX) in mitochondrial complex III-deficient CD8+ T cells restores respiration without generating ROS or proton pumping, and rescues proliferation and the exhausted phenotype but not naive or memory formation. Thus, T cell development, proliferation and memory formation have distinct requirements for mitochondrial complex III ROS.
    DOI:  https://doi.org/10.1038/s41590-025-02202-x
  3. bioRxiv. 2025 Jun 11. pii: 2025.06.09.658561. [Epub ahead of print]
    Depletion of extracellular asparagine impairs self-reactive T cells and ameliorates autoimmunity in a murine model of multiple sclerosis.
    Peter Georgiev, Sheila Johnson, Kiran Kurmi, Song-Hua Hu, SeongJun Han, Dillon Patterson, Thao H Nguyen, Linglin Huang, Dan Liang, Naomi Goldman, Thomas Conway, Hannah Creasey, Jared Rowe, Marcia C Haigis, Arlene H Sharpe.
      Amino acids play critical roles in the activation and function of lymphocytes. Here we show that the non-essential amino acid, asparagine, is essential for optimal activation and proliferation of CD4 + T cells. We demonstrate that asparagine depletion at different time points after CD4 + T cell activation reduces mitochondrial membrane potential and function. Furthermore, asparagine depletion at specific time points during CD4 + T cell differentiation reduces cytokine production in multiple CD4 + T cell subsets. In an adoptive transfer model of experimental autoimmune encephalomyelitis (EAE), myelin oligodendrocyte-specific pathogenic T helper 17 cells differentiated under Asn-deficient conditions exhibited reduced encephalitogenic potential and attenuated EAE severity. In a model of EAE induced by active immunization, therapeutic depletion of extracellular Asn significantly reduced disease severity. These results identify asparagine as a key metabolic regulator of the pathogenicity of autoreactive CD4 + T cells and suggest that targeting asparagine metabolism may be a novel therapeutic strategy for autoimmunity.
    DOI:  https://doi.org/10.1101/2025.06.09.658561
  4. bioRxiv. 2025 Jun 14. pii: 2025.06.10.658841. [Epub ahead of print]
    Accumulation of SA-βGal-High Cells in Human Naïve T Cell Compartments Reveals a Stress-Adapted, Senescent-Like State.
    Andreea Cristina Alexandru, Genesis Vega Hormazabal, Hiroyuki Matsui, Herbert Kasler, Sierra Lore, Carlos Galicia Aguirre, Andrea Roberts, Indra John Heckenbach, Ritesh Tiwari, Ryan Kwok, Sydney Becker, Eric Verdin.
      Aging is associated with a decline in immune function termed immunosenescence, characterized by accumulation of senescent-like immune cells and chronic inflammation, known as inflammaging. While senescence-associated β-galactosidase (SA-βGal) activity is a well-established senescence marker, its functional significance and the precise cellular subsets affected within the T cell compartment remain unclear. Here, we identify and characterize a previously unrecognized subset of naïve CD4⁺ and CD8⁺ T cells displaying high SA-βGal activity that significantly increases with age. Despite exhibiting hallmark features of senescence such as DNA damage, nuclear envelope disruption, loss of heterochromatin, and pronounced dysregulation of autophagy and lysosomal pathways, these SA-βGal-high naïve T cells notably lack the canonical senescence marker p21CIP1 and retain robust proliferative capacity upon activation. Remarkably, naïve CD4⁺ SA-βGal-high T cells acquire cytotoxic properties including NK-like features, granzyme secretion, and the ability to induce paracrine DNA damage in endothelial cells. Mechanistically, we demonstrate that impaired autophagic flux contributes significantly to this phenotype. Our findings address critical knowledge gaps regarding the nature and functional plasticity of senescence-like states in naïve T cells, highlighting a novel link between lysosomal-autophagic dysfunction, cellular stress adaptation, and inflammaging. Understanding this unique T cell population provides important insights into immune aging and offers potential targets to mitigate age-associated immune dysfunction and chronic inflammation.
    DOI:  https://doi.org/10.1101/2025.06.10.658841
  5. PLoS Biol. 2025 Jul 14. 23(7): e3003284
    Bi-directional metabolic reprogramming between cancer cells and T cells reshapes the anti-tumor immune response.
    Yajing Qiu, Yihan Xu, Xinyuan Ding, Congcong Zhao, Hongcheng Cheng, Guideng Li.
      Cancer cells and T cells engage in dynamic crosstalk within the tumor microenvironment (TME), shaping tumor progression and anti-tumor immunity. While cancer cells reprogram metabolism to support growth and immune evasion, T cells must adapt their metabolic states to maintain effector functions. Tumor-driven metabolic perturbations, such as nutrient depletion and accumulation of immunosuppressive metabolites, profoundly impair T cell function and fate. Conversely, metabolically reprogrammed T cells can modulate the TME and influence tumor growth. This reciprocal metabolic crosstalk represents both metabolic competition and intercellular communication, offering promising therapeutic targets.
    DOI:  https://doi.org/10.1371/journal.pbio.3003284
  6. Oncoimmunology. 2025 Dec;14(1): 2532662
    ProS1-MerTK signaling in CD4 T cells: implications for TIL expansion and functionality.
    Annina Kurzay, Sara Fresnillo Saló, Anne Rahbech, Tina Seremet, Cecilie Oelvang Madsen, Christopher Aled Chamberlain, Emilie Bülow Jensen, Viet Thy Luu, Özcan Met, Marlies J W Peeters, Per Thor Straten.
      Cancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells remains poorly understood. Here, we demonstrate that ProS1-MerTK signaling is upregulated in activated CD4 T cells, where it enhances central memory formation, metabolic fitness, and proliferation. Mechanistically, ProS1-MerTK signaling was linked to type 1 immune responses, suggesting a regulatory role in CD4 T cell polarization. Using CRISPR-Cas9-mediated knockout, we found that loss of MerTK reduced CD4 T cell fitness, function, and polarization. Furthermore, when ProS1 was added during the expansion of tumor-infiltrating lymphocytes (TILs) from advanced melanoma biopsies, it showed potential to promote favorable CD4 T cell memory and helper phenotypes, increase stemness, and reduce exhaustion - features associated with improved responses to ACT. These findings establish ProS1-MerTK as a key pathway for modulating CD4 T cell functionality and highlight its therapeutic potential to enhance TIL-based ACT outcomes.
    Keywords:  Adoptive cell therapy; T cell; TAM-receptor; immunotherapy; melanoma; tumour infiltrating lymphocyte
    DOI:  https://doi.org/10.1080/2162402X.2025.2532662
  7. Cell Rep. 2025 Jul 11. pii: S2211-1247(25)00744-2. [Epub ahead of print]44(7): 115973
    CAR-T cells containing CD28 versus 4-1BB co-stimulatory domains show distinct metabolic profiles in patients.
    Molly S Cook, Ellen King, Katie R Flaherty, Khadiza Siddika, Sophie Papa, Reuben Benjamin, Anna Schurich.
      Chimeric antigen receptor (CAR)-T cell therapy has led to unprecedented success in treating relapsed/refractory diffuse large B cell lymphoma (DLBCL). The most common CAR-T cell products currently in the clinic for DLBCL differ in their co-stimulation moiety, containing either CD28 or 4-1BB, which initiate distinct signaling pathways. Previous work has highlighted the importance of T cell metabolism in fueling anti-cancer function. We have studied the metabolic characteristics induced by CD28 versus 4-1BB co-stimulation in patient CAR-T cells ex vivo. Our data show that in patients, CD28 and 4-1BB drive significantly divergent metabolic profiles. CD28 signaling endows T cells with preferentially glycolytic metabolism supporting an effector phenotype and increased expansion capacity, while 4-1BB co-stimulation preserves mitochondrial fitness and results in memory-like differentiation. Despite the differences in metabolic programming, T cells in patients responding successfully to therapy were metabolically similar, irrespective of co-stimulator. In contrast, in non-responders, CD28- and 4-1BB-co-stimulated CAR-T cells were metabolically distinct from each other.
    Keywords:  4-1BB; CAR-T cells; CD28; CP: Cancer; CP: Metabolism; DLBCL; co-stimulation; glycolysis; lymphoma; metabolism; mitochondria; translational
    DOI:  https://doi.org/10.1016/j.celrep.2025.115973
  8. Front Immunol. 2025 ;16 1621759
    Mitochondrial unfolded protein response in regulatory T cell function: a protective mechanism in immune aging.
    Lillie Lewis, Deepa Valvi, Roberto Gedaly, Francesc Marti.
      Age-related conditions, such as neurodegenerative disease, cancer, and autoimmune disorders, are increasingly recognized as closely linked with the gradual deterioration of the immune system. Regulatory T cells (Tregs) are a small, specialized subset of T lymphocytes that play a critical role in maintaining immune homeostasis and self-tolerance. As individuals age, Treg cells demonstrate reduced capacity to suppress some autoreactive immune responses, although they largely retain their capacity to regulate effector antiviral and antitumor immunity. Unlike conventional effector T cells (Teff), which primarily derive energy from glycolysis, Tregs rely more on mitochondrial oxidative phosphorylation to fulfill their energy requirements. This metabolic profile renders them particularly sensitive to mitochondrial dysfunction, underpinning the critical role of mitochondrial protective pathways in preserving the functional integrity of Treg cells. The mitochondrial unfolded protein response (mitoUPR) is gaining special relevance among these protective mechanisms. In this review, we examine the complex interplay between immune aging and mitochondrial dynamics, with particular emphasis on the essential role of mitoUPR in supporting Treg function. We further discuss how targeting mitochondrial stress responses may offer novel therapeutic avenues for age-related diseases characterized by Treg dysfunction.
    Keywords:  aging; cell metabolism; cellular stress; immunosenescence; oxidative stress; regulatory T-cells; unfolded protein response
    DOI:  https://doi.org/10.3389/fimmu.2025.1621759
  9. bioRxiv. 2025 May 01. pii: 2025.04.28.651077. [Epub ahead of print]
    Intratumoral amino acid insufficiency limits CD8 + T-cell effector function.
    Yan-Ting Chen, Ya-Hui Lin, Jahan Rahman, Justin Cross, Natalya N Pavlova, Santosha A Vardhana.
      Loss of effector function is a hallmark of tumor-infiltrating CD8 + T-cells that have lost therapeutic efficacy. This impaired capacity occurs despite expression of transcripts encoding cytotoxic proteins, raising the possibility that post-transcriptional suppression of cytotoxic protein synthesis limits anti-tumor immunity. Whether altered protein synthesis contributes to CD8 + T-cell dysfunction has not been explored. Here we show that intratumoral amino acid availability restricts the cytotoxic capacity of CD8 + TILs by perturbing their ability to sustain protein synthesis. mRNA translation rates in antigen-specific CD8 + T-cells were rapidly and specifically suppressed within tumors but not tumor-draining lymph nodes, due to a combination of increased amino acid demand and reduced amino acid availability. Mechanistically, amino acid-dependent uncharging of tRNA Gln in T-cells persistently exposed to antigen was sufficient to suppress protein synthesis in a manner that is independent of either activation of the integrated stress response or suppression of mTORC1 activation. Finally, suppressing intracellular glutaminase activity or ectopically overexpressing the amino acid transporter SLC6A15 was sufficient to restore CD8 + T-cell effector function. These results establish a novel mechanism by which nutrient availability in the tumor microenvironment limits T-cell function and demonstrate how enhancing T cell-specific amino acid availability can sustain T-cell effector function and potentiate anti-tumor immunity.
    DOI:  https://doi.org/10.1101/2025.04.28.651077
  10. Cancers (Basel). 2025 Jul 02. pii: 2225. [Epub ahead of print]17(13):
    Regenerative Immunotherapy for Cancer: Transcription Factor Reprogramming of Tumor-Specific T Cells.
    Tyler R McCaw, Nicholas P Restifo, Kathrin Plath, Joseph G Crompton.
      Cell-based immunotherapy is a promising treatment strategy for cancer. Particularly in the case of solid tumors, however, this strategy only benefits a minority of patients. A critical limitation to immunotherapy is T cell exhaustion, a terminal differentiation state characterized by loss of self-renewal and cytotoxic capacity. For over a decade, regenerative immunology approaches to overcome exhaustion and restore stem-like features of T cells have been pursued. The reprogramming of tumor-specific T cells back to a less-differentiated, stem-like state using induced pluripotent stem cell (iPSC) technology has been viewed as a powerful and highly appealing strategy to overcome the limitations imposed by exhaustion. However, clinical translation of these approaches has been stymied by the requirement for subsequent iPSC-to-T cell re-maturation strategies, vanishingly low efficiencies, and resource-intensive cell culture protocols. In this review, we discuss the emergence of transcription factor reprogramming to iPSCs, contemporary techniques for T cell reprogramming, as well as techniques for re-differentiation into mature T cells. We discuss the potential clinical utility of T cell reprogramming and re-maturation strategies alongside progress and major roadblocks toward clinical translation. If these challenges can be addressed, transcription factor reprogramming of T cells into iPSCs and subsequent re-maturation into tumor-specific stem-like T cells may represent an incredibly efficacious approach to cancer immunotherapy.
    Keywords:  T cell exhaustion; adoptive cellular therapy; immunotherapy; stemness; transcription factor reprogramming
    DOI:  https://doi.org/10.3390/cancers17132225
  11. Front Cardiovasc Med. 2025 ;12 1631578
    Targeting the hallmarks of aging: mechanisms and therapeutic opportunities.
    Fumihiro Sanada, Shinichiro Hayashi, Ryuichi Morishita.
      Aging is a complex biological process characterized by a gradual decline in cellular and physiological function, increasing vulnerability to chronic diseases and mortality. It involves a set of interconnected mechanisms known as the hallmarks of aging, including genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, altered intercellular communication, and dysregulated nutrient sensing. These processes act at molecular, cellular, and systemic levels, contributing to age-related disorders such as neurodegeneration, cardiovascular disease, and metabolic syndromes. Emerging therapeutic strategies aim to delay or reverse aging by targeting specific hallmarks. These include senolytics to eliminate senescent cells, NAD+ boosters and mitophagy inducers to improve mitochondrial health, epigenetic reprogramming, and caloric restriction mimetics such as metformin and rapamycin to modulate nutrient-sensing pathways. Advances in regenerative medicine, gene editing, and organ cross-talk modulation are also contributing to the development of personalized, multi-targeted anti-aging therapies. Integration of omics technologies and biomarker research is expected to enhance our ability to monitor biological aging and optimize interventions for healthy longevity. This review highlights the current understanding of the hallmarks of aging and explores potential treatment strategies in light of our recent findings.
    Keywords:  aging related disease; biological aging; chronic inflammation; chronological aging; senscence
    DOI:  https://doi.org/10.3389/fcvm.2025.1631578
  12. J Mol Med (Berl). 2025 Jul 17.
    CD8 + T Cells in Gastrointestinal Cancer: a Perspective on Targeting MicroRNA.
    Zihan Yuan, Wei He, Wenjia Luo, Chunxia Huang, Miao Li, Jie You, Jiaqiang Wu, Kangping Yang, Liang Yang.
      Gastrointestinal cancer, which is highly prevalent globally, constitutes a major threat to human health and life. The discovery of PD-L1/PD-1 has revolutionized immunotherapy, which has led to a shift in attention toward the antitumor functions of CD8 + T cells. CD8 + T cells are crucial effector cells in antitumor immunity, yet their functionality undergoes profound changes within the tumor microenvironment (TME). In the TME, gene mutations in cancer cells serve as initiating factors, remodeling the functions of various cells and the composition of noncellular substances. Cancer cells induce functional changes in other cells within the TME to favor their survival, notably impacting crucial antitumor effector cells such as CD8 + T cells, thereby furthering tumor progression. However, how tumor cells remodel CD8 + T cells remains inadequately understood, and targeted therapies against immune checkpoints face increasing challenges. An increasing number of findings suggest that miRNAs play a critical role in the process of remodeling CD8 + T cell function in tumors. Tumor cells regulate the expression of their own miRNAs to control the expression of surface molecules, modulate the release of secreted factors, or, through miRNA-containing exosomes, communicate with and remodel the function of CD8 + T cells. Elucidating the communication between CD8 + T cells and gastrointestinal cancer cells from a miRNA perspective to explain the shift of CD8 + T cells toward favorable types of tumors may inspire new therapeutic strategies. KEY MESSAGES: MicroRNAs regulate CD8+ T cells function in gastrointestinal cancers. MicroRNAs involve in crosstalk of gastrointestinal cancers with CD8+ T cells. MicroRNAs involve in crosstalk of the gastrointestinal immune microenvironment with CD8+ T cells. Focus on the application of targeted microRNA drugs and microRNA delivery strategies in gastrointestinal cancers.
    Keywords:  CD8 + T cell; Delivery system; Gastrointestinal cancer; MicroRNA; PD-L1; TME
    DOI:  https://doi.org/10.1007/s00109-025-02574-5
  13. Geroscience. 2025 Jul 16.
    Nicotinamide riboside treatment enhances stress sensitivity and modulates hematological dynamics in aged mice.
    Luka Culig, Amogh Kashyap, Wakako Kuribayashi, Quia C Claybourne, Isabel Beerman.
      Nicotinamide riboside (NR) is a precursor to NAD+, a vital molecule for cellular energy metabolism whose levels decline with age. Aging is associated with loss of cognitive and immune function, alterations in hematological parameters, and increased vulnerability to stress. Although NR supplementation can mitigate age-related declines, it remains uncertain whether these positive effects persist when the organism is exposed to chronic physiological stress. We investigated this by exposing aged mice to NR supplementation alongside daily physiological stress and assessed various indices before and after treatment. Our results revealed that 6 weeks of NR supplementation protected against stress-induced thrombocytopenia and increased the frequencies of B and T cells. However, NR also heightened stress sensitivity, as evidenced by increased anxiety-like behaviors, while not affecting cognitive function. These findings suggest a dual role for NR in potentially enhancing immune function while exacerbating behavioral responses to stress. Future research on NR should consider stress as a variable to optimize its therapeutic usage in aging populations.
    Keywords:  Aging; Anxiety; NAD+ ; Nicotinamide riboside; Stress
    DOI:  https://doi.org/10.1007/s11357-025-01793-5
  14. bioRxiv. 2025 Jun 28. pii: 2025.01.02.631038. [Epub ahead of print]
    CD38 expression by neonatal human naïve CD4 + T cells shapes their distinct metabolic state and tolerogenic potential.
    Laura R Dwyer, Andrea M DeRogatis, Sean Clancy, Victoire Gouirand, Charles Chien, Elizabeth E Rogers, Scott P Oltman, Laura L Jelliffe-Pawlowski, Susan V Lynch, Rachel L Rutishauser, Allon Wagner, Alexis J Combes, Tiffany C Scharschmidt.
      Neonatal life is marked by rapid antigen exposure, necessitating establishment of peripheral immune tolerance via conversion of naïve CD4 + T cells into regulatory T cells (Tregs). Here, we demonstrate heighted capacity for FOXP3 expression and tolerogenic function among cord blood versus adult blood naive CD4 + T cells and that this is linked to their unique metabolic profile and elevated expression of the NADase, CD38. Early life naïve CD4 + T cells demonstrate a metabolic preference for glycolysis, which directly facilitates their differentiation trajectory. We reveal an age-dependent gradient in CD38 levels on naïve CD4 + T cells and show that high CD38 expression contributes to both the glycolytic state and tolerogenic potential of neonatal CD4 + T cells, effects that are mediated at least in part via the NAD-dependent deacetylase SIRT1. Thus, the early life window for peripheral tolerance in humans is critically enabled by the immunometabolic state of the naïve CD4 + compartment.
    DOI:  https://doi.org/10.1101/2025.01.02.631038
  15. bioRxiv. 2025 May 06. pii: 2025.04.24.650529. [Epub ahead of print]
    Activating the CXCR3/CXCL10 pathway overrides tumor immune suppression by enhancing immune trafficking and effector cell priming in head and neck squamous cell carcinoma.
    Cheyanne K Shinn, Robert Saddawi-Konefka, Catherina L Salanga, Shiruyeh Schokrpur, J Silvio Gutkind, Tracy M Handel.
      The immune-suppressive nature of the tumor microenvironment (TME) has limited the impact of immune checkpoint blockade in many cancers, often by restricting the infiltration and activation of anti-tumoral CD8+ T, CD4+ T, and NK cells. Here, we utilized murine models of head and neck squamous cell carcinoma and demonstrated that intratumoral (IT) delivery of CXCL10 drives tumor elimination and inhibits recurrence. CD8+ T cells recruited to tumors display enhanced activation, increased tumor antigen specificity, and decreased markers of T cell exhaustion, indicating that CXCL10 not only directs cell migration, but also enhances T cell effector functions. Despite delivery of CXCL10 into tumors, CD8+ and CD4+ T cells also show enhanced presence and proliferation in tumor-draining lymph nodes (TdLNs), consistent with antigen presentation and trafficking of these cells between tumors and TdLNs. CXCL10 also stunts angiogenesis and lymphangiogenesis within the TME, which likely contributes to its antitumoral effects. Finally, enhanced tumor clearance was observed by combining IT CXCL10 and anti-PD-1. Together, these findings provide the rationale for the clinical evaluation of CXCL10 as a strategy to enhance the efficacy of immunotherapy.
    SUMMARY: CXCL10 suppresses tumor growth and promotes immune memory by recruiting T and NK cells into the tumor microenvironment, promoting tumor-specific antigen recognition and effector functions, slowing T cell exhaustion, and inhibiting angiogenesis. CXCL10 directly and indirectly mobilizes an immune cell network that together supports an anti-tumoral microenvironment.
    DOI:  https://doi.org/10.1101/2025.04.24.650529
  16. Proc Natl Acad Sci U S A. 2025 Jul 22. 122(29): e2427254122
    T lymphocyte-specific deletion of SHP1 and SHP2 promotes activation-induced cell death of CD4+ T cells and impairs antitumor response.
    Connor J R Foster, Jasper Du, Oscar Pundel, Mitchell J Geer, Ryan C Ripert, Jia Liu, Taylor A Heim, Kiyomi Y Araki, Amanda W Lund, Jun Wang, Benjamin G Neel.
      SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naïve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role. Surprisingly, loss of SHP2 alone in T cells enhanced the antitumor effects of anti-PD-1 antibodies, whereas there was no effect of SHP1 deletion. Also unexpectedly, the absence of both PTPs resulted in poorer tumor control and failure to respond to Programmed Cell Death Protein 1 (PD-1) blockade, associated with reduced frequency and activation of T cells and dendritic cells. Mechanistic studies revealed that CD4+, but not CD8+, T cells lacking SHP1 and SHP2 show increased activation-induced cell death upon anti-CD3/CD28 stimulation. Adoptive transfer of antigen-specific CD4+ T cells restored normal levels of tumor control in mice lacking both PTPs. Together, our results demonstrate that SHP1 or SHP2 is required to prevent activation-induced cell death of CD4+ T cells and is critical for tumor immunity, raising the possibility that inhibition of SHP2 might augment the therapeutic efficacy of PD-1-based immune therapy.
    Keywords:  ITIM; PD-1; PTPN11; PTPN6; tumor immunity
    DOI:  https://doi.org/10.1073/pnas.2427254122
  17. J Immunother Cancer. 2025 Jul 15. pii: e011657. [Epub ahead of print]13(7):
    Disruption of cell-intrinsic PCSK9 enhances the antitumor efficacy of CD8+ T cells.
    Bing Liu, Letong Cai, Yiwen Yan, Chengzhou Mao, Xiaohui Zhang, Yudan He, Si Chen, Lizhong Liu, Zhe Xu, Long Xu, FuSheng Wang, Li Yu, A H Jan Danser, Xifeng Lu, Shaojun Xing.
       BACKGROUND: Tumor-derived proprotein convertase subtilisin/kexin type 9 (PCSK9) facilitates tumor progression, but the role of immune cell-intrinsic PCSK9 in tumor control remains unclear.
    METHODS: Orthotopic models of pancreatic cancer and melanoma in Pcsk9-deficient mice were established and tumor-infiltrating immune cells were analyzed using single-cell RNA sequencing and flow cytometry. The effect of genetic disruptions of PCSK9 on murine CD8+ T cells and human chimeric antigen receptor (CAR)-T cells was evaluated both in vitro and in vivo.
    RESULTS: Ablation of host Pcsk9 remarkably suppressed tumor growth and prolonged the survival of tumor-bearing mice, while tumor cells still express PCSK9. The enhanced tumor suppression in Pcsk9-deficient mice depended on CD8+ T cells. Notably, PCSK9 expression was induced in CD8+ tumor-infiltrating lymphocytes (TILs). Consequently, Pcsk9 ablation potentiated the antitumor capacity of CD8+ T cells, showing increased intratumoral infiltration and improved cytotoxic function, along with higher proportions of both effector-memory precursor exhausted (TPEX) and terminally exhausted (TTEX) CD8+ TILs. Additionally, disruption of PCSK9 in both murine CD8+ T cells and human CAR-T cells, synergistic with PD-1 blockade, promoted tumor suppression.
    CONCLUSION: These findings indicate that PCSK9 inhibits the antitumor function of CD8+ T cells, suggesting it may be a promising target for enhancing T-cell-based cancer immunotherapy.
    Keywords:  Adoptive cell therapy - ACT; Immunotherapy; T cell
    DOI:  https://doi.org/10.1136/jitc-2025-011657
  18. Nat Rev Cancer. 2025 Jul 11.
    Cancer progression through the lens of age-induced metabolic reprogramming.
    Felicia Lazure, Ana P Gomes.
      Ageing is an important risk factor for cancer incidence and augments cancer progression. A shared hallmark of ageing and cancer is metabolic reprogramming, which has been suggested to be not only a cause but also a consequence of ageing. Strikingly, many age-regulated pathways are known to also drive tumour progression, suggesting that metabolic reprogramming connects ageing and tumorigenic processes and shapes whether malignant phenotypes manifest, thrive and evolve. With the rising average age of the world population, understanding how age-related changes in the body influence cancer progression is of paramount importance. In this Perspective, we discuss the metabolic changes that occur with ageing and their potential links with tumour initiation and progression and the development of metastatic disease. Finally, we discuss age-induced metabolic divergences that cause racial disparities and their consequences for the tumorigenic process.
    DOI:  https://doi.org/10.1038/s41568-025-00845-4
  19. bioRxiv. 2025 Jun 18. pii: 2025.03.03.641115. [Epub ahead of print]
    Small molecule modulators of TOX protein re-invigorate T cell activity.
    Bocheng Wu, Heng Jui Chang, Prashant Singh, Alexander Hostetler, Yichen Xiang, Shenghao Guo, Fiona Yihan Wang, Julia J Zhong, Becky S Leifer, Richard P Schiavoni, Nan Jiang, Amit Choudhary, Peter M K Westcott, Angela N Koehler.
      The TOX protein (thymocyte selection-associated high mobility group box) is a critical transcription factor implicated in both T acute lymphoblastic leukemia (T-ALL) and CD8 + T cell exhaustion. Gene perturbation studies suggest that inhibiting TOX may have therapeutic implications for both leukemia and T cell exhaustion. However, due to its complex molecular mechanisms and intrinsically disordered structure, TOX has not been effectively targeted by small molecules to date. In this study, we used small molecule microarray (SMM) screening and biochemical assays to identify a series of TOX protein-protein interaction (PPI) inhibitors. We identified KI-TOX-A3 as a TOX protein binder and potent TOX PPI inhibitor. In T-ALL, KI-TOX-A3 revealed selective cytotoxicity and proteosome-dependent TOX degradation. In CD8 + T cells, KI-TOX-A3 potently reversed T cell exhaustion by decreasing surface inhibitory receptors, increasing expression of effector cytokines, and enhancing cancer cell killing activity. We also demonstrate the utility of KI-TOX-A3 to probe potential epigenetic regulatory mechanisms of TOX via KAT7 acetylation in T cells.
    DOI:  https://doi.org/10.1101/2025.03.03.641115
  20. Nat Immunol. 2025 Jul 14.
    IL-4 impairs the formation of skin-resident memory CD8+ T cells.
    Rut Mora-Buch, Maisie E Lake, Andrea Sama, Alexandra Y Chasse, Hasan Akbaba, Vinidhra Mani, Shannon K Bromley.
      Local cytokines, including TGFβ, drive CD8+ tissue-resident memory T (TRM) cell differentiation and long-term persistence within tissues. However, the signals that prevent CD8+ TRM cell formation are not well defined. Here we found that IL-4 suppressed CD8+ T cell acquisition of an epithelial TRM cell phenotype. IL-4 inhibited the expression of TGFβ-induced CD103 and CD49a and increased the expression of Eomes by activated CD8+ T cells in vitro and in vivo. This change in phenotype was correlated with prolonged downregulation of TGFβRII, decreased expression of pSmad2/3 and increased expression of inhibitory Smad7. Naive CD8+ T cells exposed to IL-4 during activation exhibited impaired cutaneous CD103+CD8+ TRM cell formation. Additionally, IL-4 produced within atopic dermatitis lesions decreased the expression of CD103 in infiltrating CD8+ T cells and reduced CD8+ TRM cell formation, resulting in reduced protection from cutaneous herpes simplex virus infection. Together, these findings reveal that IL-4 decreases the responsiveness of CD8+ T cells to TGFβ, resulting in impaired formation of CD8+ TRM cells and impaired CD8+ TRM cell-mediated protection from local infection.
    DOI:  https://doi.org/10.1038/s41590-025-02207-6
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