bims-imseme Biomed News
on Immunosenescence and T cell metabolism
Issue of 2025–08–31
thirty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research



  1. Trends Immunol. 2025 Aug 22. pii: S1471-4906(25)00181-4. [Epub ahead of print]
      Metabolic reprogramming and signaling are key orchestrators of T cell immunity. Recent studies have illustrated important roles for intracellular organelles, especially mitochondria and lysosomes, in enforcing T cell metabolism and signaling in response to various extracellular cues. As such, mitochondrial and lysosomal function contributes to adaptive immunity by regulating T cell activation, differentiation, and functional adaptation. In this Review, we discuss how the interplay between organelle biology and metabolism instructs T cell-mediated immunity, with a particular focus on mitochondria and lysosomes. We also summarize how mitochondria and lysosomes, or their crosstalk with other organelles, orchestrate downstream signaling processes and functional reprogramming of T cells. We conclude with a discussion of the pathophysiological outcomes associated with dysregulation of these organelles.
    Keywords:  T cells; immunometabolism; lysosomes; metabolic signaling; mitochondria; organelle crosstalk
    DOI:  https://doi.org/10.1016/j.it.2025.07.014
  2. Cell Rep Med. 2025 Aug 20. pii: S2666-3791(25)00383-0. [Epub ahead of print] 102310
      T cell dysfunction with age underlies an increased incidence of cancer in elderly individuals; however, how T cell aging is triggered in the tumor microenvironment is unclear. Here, we show that an age-associated reduction in adipocyte-derived leptin contributes to the accumulation of tumor-infiltrating senescent CD8+ T cells. Single-cell profiling of human and mouse cancer tissues reveals that the frequency of intratumoral senescent CD8+ T cells increases with age, leading to a weak antitumor effect. Moreover, decreased levels of adipocyte-derived leptin are an indispensable factor for CD8+ T cell aging. Leptin signaling prevents p38-dependent CD8+ T cell senescence. Furthermore, plasma leptin levels are negatively related to intratumoral CD8+ T cell senescence in cancer patients. Our findings identify an unappreciated interplay between metabolic perturbation and T cell aging and suggest that modulating adipocyte-derived leptin levels may be a promising therapeutic strategy for older cancer patients.
    Keywords:  CD8(+) T cells; T cell senescence; aging; antitumor immunity; leptin
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102310
  3. Cancer Res. 2025 Aug 21.
      The fate of CD8⁺ T cells is sculpted not only by antigenic stimulation and cytokine milieu but, increasingly, by metabolic context. In their recent Nature Immunology study, Sharma and colleagues report a previously underappreciated and temporally constrained nutrient-sensing mechanism where methionine (Met) availability during the earliest minutes of T cell receptor (TCR) engagement exerts durable control over T cell function, exhaustion, and anti-tumor efficacy. Their findings expose a critical metabolic window, within just 30 minutes of activation, during which extracellular Met shapes intracellular signaling and transcriptional fate decisions through a post-translational mechanism involving arginine methylation of the calcium-activated potassium channel KCa3.1. These findings open the door to timed interventions that modulate methionine and potentially enhance T cell responses.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-25-3656
  4. Nat Immunol. 2025 Aug 22.
      Stem-like progenitor CD8+ T (TPRO) cells sustain cytotoxic immunity during chronic infection and cancer through quiescence, multipotency and self-renewal, hallmarks shared with memory T cells. However, how these properties are maintained under persistent antigen stimulation remains unclear. Here we identify the genomic organizer SATB1 as selectively enriched in both TPRO and memory CD8+ T cells. Given its role in promoting quiescence in hematopoietic stem cells, we hypothesized that SATB1 supports CD8+ T cell stemness. Using CD8+ T cell-specific CRISPR deletion of the Satb1 gene, we show that SATB1 is essential for maintaining TPRO cells during chronic lymphocytic choriomeningitis virus infection and for memory CD8+ T cell formation during acute infection. Multi-omic profiling revealed that SATB1 regulates the chromatin accessibility, transcriptional activity and genome architecture of stemness-associated genes including Tcf7, Bach2 and Myb. These findings reveal a critical role for SATB1 in preserving the transcriptional and epigenetic programs that sustain the stem-like state of antigen-specific CD8+ T cells.
    DOI:  https://doi.org/10.1038/s41590-025-02257-w
  5. J Ginseng Res. 2025 Sep;49(5): 564-573
       Background: Mitochondrial function is essential for immune cell regulation, and its decline is linked to aging and chronic diseases. Impaired activity contributes to inflammation and reduced immunity. This study explores Red ginseng extract (RGE)'s potential in enhancing mitochondrial function and immune cell viability, offering benefits in mitigating immunosenescence.
    Methods: T cells and macrophages from young (12-week-old) and aged (20-month-old) mice were treated with RGE to assess mitochondrial function and cell viability. Flow cytometry evaluated immune cell populations and cytokine expression in splenocytes, while single cell transcriptomics analyzed RGE-induced transcriptional changes in T cells and macrophages.
    Results: RGE treatment improved mitochondrial oxygen consumption rate and glycolytic function in CD4+ and CD8+ T cells from both young and old mice, though effects were more pronounced in young cells. In aged mice, RGE administration resulted in higher proportions of naive T cells and reduced expression of senescence and exhaustion markers. Flow cytometry analysis indicated a decrease in pro-inflammatory cytokines IFN-γ and TNF-α in T cells, along with a reduction in IL-17-producing T cells. Single cell transcriptome analysis revealed downregulation of aging markers (Cd28 and Cd27) and increased expression of mitochondrial complex genes, supporting RGE's role in enhancing mitochondrial function.
    Conclusion: RGE treatment enhances mitochondrial function and attenuates T cell senescence and exhaustion in aged immune cells, likely contributing to immune resilience against age-associated inflammation. This study highlights the potential of RGE as a therapeutic intervention for improving immune function and reducing the effects of immunosenescence, offering valuable insights into mitigating age-related immune decline.
    Keywords:  Aging; Immunosenescence; Mitochondria; Red ginseng extract; T cell
    DOI:  https://doi.org/10.1016/j.jgr.2025.05.004
  6. J Hematol Oncol. 2025 Aug 22. 18(1): 81
      Immunosenescence, the age-related decline in immune function, profoundly impacts cancer progression and therapeutic outcomes by fostering a tumor-promoting microenvironment and impairing immune surveillance. This review delineates eleven molecular hallmarks of immunosenescence, including genomic instability, telomere attrition, epigenetic dysregulation, mitochondrial dysfunction, and chronic inflammation, which collectively drive immune cell dysfunction and systemic immunosuppression. Aging reshapes the tumor microenvironment (TME) through recruitment of immunosuppressive cells, senescence-associated secretory phenotypes (SASP), and metabolic reprogramming, contributing to therapy resistance and poor prognosis in elderly patients. While immunotherapies such as immune checkpoint inhibitors (ICIs) and chimeric antigen receptor T-cell immunotherapy (CAR-T) cells show promise, their efficacy in aging populations is limited by T cell exhaustion, myeloid bias, and altered intercellular communication. Emerging strategies-including senolytics, epigenetic modulators (e.g., histone deacetylase (HDAC) inhibitor), and metabolic interventions (e.g., spermidine, nicotinamide mononucleotide (NMN))-highlight potential avenues to rejuvenate aged immunity. Single-cell multi-omics (single cell RNA-seq, single cell ATAC-seq) further unravel immune cell heterogeneity, revealing tissue-specific chromatin accessibility dynamics and novel targets like interleukin-34 (IL-34) for microglia-mediated neuroinflammation. However, challenges persist in translating preclinical findings to clinical practice, necessitating age-tailored trials and biomarker-driven approaches. By integrating mechanistic insights with translational innovations, this review underscores the urgency of addressing immunosenescence to optimize cancer immunotherapy for aging populations, ultimately bridging the gap between aging biology and precision oncology.
    DOI:  https://doi.org/10.1186/s13045-025-01735-w
  7. JCI Insight. 2025 Aug 22. pii: e187680. [Epub ahead of print]10(16):
      T cells rely on different metabolic pathways to differentiate into effector or memory cells, and metabolic intervention is a promising strategy to optimize T cell function for immunotherapy. Pyruvate dehydrogenase (PDH) is a nexus between glycolytic and mitochondrial metabolism, regulating pyruvate conversion to either lactate or acetyl-CoA. Here, we retrovirally transduced pyruvate dehydrogenase kinase 1 (PDK1) or pyruvate dehydrogenase phosphatase 1 (PDP1), which control PDH activity, into CD8+ T cells to test effects on T cell function. Although PDK1 and PDP1 were expected to influence PDH in opposing directions, by several criteria they induced similar changes relative to control T cells. Seahorse metabolic flux assays showed both groups exhibited increased glycolysis and oxidative phosphorylation. Both groups had improved primary and memory recall responses following infection with murine gammaherpesvirus-68. However, metabolomics using labeled fuels indicated differential usage of key fuels by metabolic pathways. Importantly, CD8+ T cell populations after B cell lymphoma challenge were smaller in both groups, resulting in poorer protection, which was rescued by glutamine and acetate supplementation. Overall, this study indicates that PDK1 and PDP1 both enhance metabolic capacity, but the context of the antigenic challenge significantly influences the consequences for T cell function.
    Keywords:  Adaptive immunity; Immunology; Immunotherapy; Metabolism
    DOI:  https://doi.org/10.1172/jci.insight.187680
  8. J Immunol. 2025 Aug 22. pii: vkaf165. [Epub ahead of print]
      CD8 T cell exhaustion has been reported in mice susceptible to Toxoplasma gondii infection. While the differentiation of CD8 exhausted subsets has been extensively reported, most of these studies have been conducted in chronic viral and cancer models. During chronic T. gondii infection, phenotypic and transcriptomic analyses of the polyclonal antigen-specific CD8 T cell response characterize 4 populations based on KLRG1 and CD62L expression. Pop1 (KLRG1+CD62Llo) bears the attributes of a terminal effector subset, and pop2 (KLRG1-CD62Llo) is similar to effector memory CD8 T cells. Akin to chronic viral infection and cancer systems, pop3 (KLRG1-CD62Lhi) exhibits the characteristics of stem-like progenitor CD8 T cells (high Tcf7, Slamf6, and Cxcr5 expression), whereas pop4 (KLRG1+CD62Lhi) closely resembles a transitory subset (elevated Tbx21, low Tcf1, and Tox expression). During chronic viral infection, the stem-like progenitor CD8 T cells transition into a terminally differentiated exhausted subset via an intermediate population. However, in our system, pop3 (KLRG1-CD62Lhi) generates pop4 (KLRG1+CD62Lhi), which does not convert into a conventional terminally differentiated exhausted subset but instead transitions into effector pop1 (KLRG1+CD62Llo). Notably, during the chronic phase of the infection, pop1 cannot retain its functionality, irrespective of its origin, which may hamper its ability to control reactivation. Our observations emphasize that the differentiation of exhausted CD8 T cells in non-viral infections, like chronic toxoplasmosis, follows a different pattern than established models and highlights the need to develop new immune strategies better tailored for a broad range of pathogens.
    Keywords:  CD8 T cells; Toxoplasma gondii; exhaustion; intermediate CD8 T cells; memory T cells; stem-like T cells
    DOI:  https://doi.org/10.1093/jimmun/vkaf165
  9. Cell Death Dis. 2025 Aug 23. 16(1): 640
      The anti-tumor function of T cells in the ovarian cancer (OC) microenvironment influences the prognosis of OC. Previous studies have indicated that metabolic competition among microenvironmental cells regulates the function of immune cells. Recent research has shown that NAD+ metabolism plays a significant role in modulating immune cell activity, and increasing NAD+ levels is a promising therapeutic strategy to enhance the effector functions of immune cells. However, the regulatory mechanisms of NAD+ metabolism on the anti-tumor function of T cells in the OC microenvironment remain unclear. This study found that exogenous supplementation of NAM to increase NAD+ levels in T cells significantly activates the endogenous p-STING axis and downstream interferon signaling within T cells, thereby enhancing T cell activation and anti-tumor effects. Concurrently, we discovered that elevated NAD+ levels promote the retention of STING on the Golgi apparatus. Mechanistically, we elucidated that the increase in NAD+ levels mediated by NAM downregulates the expression of SURF4 protein through ubiquitination and degradation, subsequently activating the p-STING axis in T cells. Furthermore, exogenous NAM supplementation can further enhance the activation of the T cell STING axis by PARP inhibitor (PARPi)-treated OC cells, and the combination of PARPi and NAM significantly augments the anti-tumor function of T cells, inhibiting the progression of OC. Our findings provide a molecular basis for the regulation of T cell anti-tumor function by NAD+, highlighting the potential strategy of targeting T cell metabolic reprogramming for the treatment of OC.
    DOI:  https://doi.org/10.1038/s41419-025-07939-9
  10. Pharmacol Res. 2025 Aug 21. pii: S1043-6618(25)00353-6. [Epub ahead of print]220 107928
      T cell activation, triggered by antigen recognition via the T cell receptor, initiates crucial physiological changes necessary for proliferation and survival. This process encompasses epigenetic modifications that open chromatin for transcription factor binding, transcriptomic shifts activating key genes, and structural adaptations, including increased cell size and cytoskeletal changes. Activated T cells experience heightened metabolic demands, requiring efficient nutrient uptake primarily via Solute Carrier (SLC) transporters. These transporters, regulated by transcription factors such as c-Myc, HIF-1α, NF-κB, and mTORC1, optimize nutrient acquisition to support glycolysis and macromolecule synthesis. In the tumor microenvironment, however, aberrant tumor metabolism depletes nutrients and produces metabolites that impair T cell function and reduce the efficacy of adoptive cell therapies, which are not metabolically adapted to survive in such hostile conditions. Modulating SLC transporters presents a promising strategy to enhance chimeric antigen receptor T cell (CAR-T) effectiveness by improving their persistence and antitumor activity. Personalized approaches targeting SLC transporters, tailored to the metabolic profiles of specific tumor types, are crucial for maximizing the therapeutic potential of adoptive T cell therapies. This review explores the critical role of SLC transporters in CAR-T cell functionality and discusses strategies to optimize their expression and activity within the challenging TME.
    Keywords:  CAR-T cells; Immunotherapy; Solid tumors; Solute carrier transporters; Tumor metabolism; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.phrs.2025.107928
  11. Nat Metab. 2025 Aug 22.
      In the tumour microenvironment, accumulated lactic acid (LA) promotes tumour immune evasion by facilitating regulatory T cell (Treg) immunosuppressive function and restraining CD8+ T cell cytotoxicity, but the underlying mechanism remains elusive. Here we report that transcriptional factor MondoA-induced thioredoxin interacting protein (TXNIP) transcription is a common feature of both Treg and CD8+ T cells in response to lactic acid. In contrast to reduction in immunosuppressive capacity in MondoA-deficient Treg cells, loss of MondoA enhanced CD8+ T cell cytotoxic function in the lactic-acid-induced immunosuppressive microenvironment, by restoring glucose uptake and glycolysis. Mechanistically, lactic acid relied on sentrin/SUMO-specific protease 1 (SENP1) to stimulate the MondoA-TXNIP axis, which impaired TCR/CD28-signal-induced CD8+ T cell activation. Importantly, targeting the MondoA-TXNIP axis potentiated antitumour immunity in multiple cancer types and synergized with anti-PD-1 therapy to promote effective T cell responses in colorectal cancer. Our results demonstrate that the MondoA-TXNIP axis is a promising therapeutic target for improving cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s42255-025-01347-1
  12. Signal Transduct Target Ther. 2025 Aug 26. 10(1): 271
      The intake of sugars, especially glucose and fructose, has significantly increased with the change of lifestyle. Excessive intake of sugar has been proven to be associated with tumors and inflammatory diseases. Fructose directly mediates innate immune responses; however, whether it can directly regulate T-cell immunity remains unknown. We show that high fructose consumption accelerates the development of inflammatory bowel disease (IBD) by promoting the generation of T helper 1 (Th1) and T helper 17 (Th17) cells. It was demonstrated that fructose promotes the differentiation of Th1 and Th17 cells directly by enhancing mechanistic target of rapamycin complex 1 (mTORC1) activation through the glutamine metabolism-dependent pathway. Reactive oxygen species (ROS)-induced activation of transforming growth factor-β (TGF-β) is also involved in fructose-induced Th17 cell generation. Moreover, metformin can reverse Th1 and Th17 cell generation induced by fructose by suppressing mTORC1 activation and reducing ROS-mediated TGF-β activation. Finally, we identified metformin as an in vivo therapeutic drug for relieving high fructose consumption-induced T-cell inflammation and colitis aggravation. Our study revealed a previously unknown adverse effect of high fructose consumption in disrupting immune homeostasis and exacerbating IBD by directly promoting T-cell immunity, and showed metformin is a potential therapeutic for reversing the T cell immune imbalance caused by long-term high fructose consumption.
    DOI:  https://doi.org/10.1038/s41392-025-02359-9
  13. Cell Rep. 2025 Aug 25. pii: S2211-1247(25)00948-9. [Epub ahead of print]44(9): 116177
      Upon antigenic stimulation, CD4+T cells undergo clonal expansion elevating their bioenergetic demands and utilization of nutrients like glucose and glutamine. The nuclear factor erythroid-2-related factor 2 (Nrf2) is a well-known regulator of oxidative stress, but its involvement in modulating the metabolism of CD4+T cells remains unexplored. We report that Nrf2 protein levels are temporally regulated in activated CD4+T cells, with elevated expression during early activation followed by a decline. T cell-specific constitutive activation of Nrf2, by deletion of its negative regulator Keap1, enhances early activation and interleukin-2 (IL-2) expression, upregulates T cell receptor (TCR) signaling, and increases activation-driven expansion of CD4+T cells. Mechanistically, elevated Nrf2 activity in activated CD4+T cells increases chromatin accessibility and proliferation-associated gene expression. Metabolically, high Nrf2 alters glucose metabolism and promotes glutamine metabolism via glutaminolysis to support CD4+T cell hyperproliferation. In summary, we elucidate the role of Nrf2 beyond traditional antioxidation in modulating the activation-driven expansion of CD4+T cells by influencing their nutrient metabolism and gene expression.
    Keywords:  CP: Immunology; CP: Metabolism; T cell activation; T cell expansion; adaptive immune cells; antioxidation; immunometabolism
    DOI:  https://doi.org/10.1016/j.celrep.2025.116177
  14. Oncogene. 2025 Aug 26.
      Tryptophan (Trp) metabolites have emerged as key regulators of host tumor immunity and cancer patient response to immunotherapy. However, the function of and mechanism underlying Trp in tumor-activated CTLs in the tumor microenvironment are incompletely understood. Using a defined co-culture system of tumor-specific CTLs and cognate antigen-expressing tumor cells, we performed a genome-wide metabolomics screening and observed that Trp level is elevated in the tumor cell-activated CTLs. Parallel genome-wide RNA-Sequencing and ATAC-Sequencing analysis determined that tumor-specific CTLs respond to tumor cells by transcriptionally activating Slc7a5 expression. Pharmacological inhibition of Slc7a5 decreased Trp uptake in tumor-activated CTLs and suppressed CTL lytic activity in killing tumor cells in vitro. Mice with Slc7a5 deficiency only in T cells exhibited diminished level of tumor-infiltrating T cells and increased tumor growth and metastasis. scRNA-sequencing analysis revealed that Slc7a5 deficiency resulted in decreased activation of the aryl hydrocarbon receptor (AhR) pathway and repressed FasL expression in tumor-infiltrating T cells. Chromatin immunoprecipitation determined that AhR binds to Faslg promoter in tumor-infiltrating T cells. FasL blockade therapy promotes tumor growth and metastasis in tumor-bearing mice. In human cancer patients, AhR expression correlates with FasL expression in tumor-infiltrating T cells. Furthermore, FasL expression is correlated with patient response to pembrolizumab and survival time. Our finding determines that the Slc7a5-Trp metabolic pathway activates AhR to up-regulate FasL expression in tumor-infiltrating T cells to sustain CTL anti-tumor immunity. Targeting CAR-T cells to up-regulate Slc7a5 to maintain T cell proliferation and function therefore could be a promising direction in cancer immunotherapy.
    DOI:  https://doi.org/10.1038/s41388-025-03543-5
  15. Cell Rep. 2025 Aug 22. pii: S2211-1247(25)00952-0. [Epub ahead of print]44(9): 116181
      B cell follicles (BCFs) in the lymph node are a major sanctuary for HIV reservoirs. Immune regulatory mechanisms hindering cytolytic CD8+ responses at these sites are poorly characterized, likely enabling HIV persistence. Spatial transcriptomics and high-dimensional histocytometry were used to define CD8+ T cell function and immune regulation in lymph node (LN) follicles of people living with HIV (PLWH), at various stages of antiretroviral therapy (ART) treatment. Histocytometry demonstrated that CD8+ T cells infiltrating BCFs mostly lacked granzyme B expression, coinciding with reduced chromatin access at cytolytic gene loci in dissociated lymph node cells. Spatial transcriptomics confirmed the immune regulatory microenvironment of HIV-infected BCFs, particularly exhibiting upregulation of HLA-E. Additional fluorescence-activated cell sorting (FACS) analysis identified a subset of LN CD8+ T cells expressing the NKG2A-interacting partner of HLA-E, with reduced granzyme B expression. These findings suggest that regulation of follicular CD8+ T cells at the HLA-E-NKG2A axis may be a key mechanism for HIV immune evasion.
    Keywords:  CD8 T cell regulation; CP: Immunology; HIV reservoir; HLA-E; lymph node immune regulation; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2025.116181
  16. Sci Adv. 2025 Aug 22. 11(34): eadx5687
      Memory CD8 T cells provide long-lasting immunity, but their developmental origins remain incompletely defined. Growing evidence suggests that functional heterogeneity exists within the naïve T cell pool, shaping lineage potential before antigen stimulation. Here, we identify a subpopulation of naïve CD8 T cells expressing death-associated protein-like 1 (Dapl1) that contains preprogrammed precursors biased toward memory differentiation. The differentiation of these precursors is independent of Dapl1 but relies on the transcription factor B-cell lymphoma/leukaemia 11b (Bcl11b), resulting in the generation of Dapl1+ central memory-like CD8 T cells after infection and stem-like memory cells in cancer. Dapl1+ naïve T cells originate among mature thymocytes and gradually appear in the periphery postnatally. Peripheral Dapl1+ and Dapl1- populations show limited plasticity, supporting a thymic-imprinting model. These findings reveal a developmentally imprinted subset of naïve CD8 T cells committed to memory fate, uncovering an alternative pathway for memory T cell generation offering new avenues for therapeutic application.
    DOI:  https://doi.org/10.1126/sciadv.adx5687
  17. Mol Ther. 2025 Aug 20. pii: S1525-0016(25)00654-9. [Epub ahead of print]
      Immune tolerance restricts the number of T cells with significant affinity for self-tumor-associated antigens (TAAs), thereby limiting successful cancer immunotherapy through an inability to generate populations of high-affinity anti-tumor T cells. In contrast, viral infection/vaccination primes and expands high-affinity effector and memory T cells against viral antigens. We show here that it is possible to exploit population-wide preexisting, anti-viral memory recall responses against SARS-CoV-2 antigens to focus a high-affinity, immunodominant T cell response into tumors by oncolytic virus (OV)-mediated or chimeric antigen receptor (CAR)-mediated delivery of viral antigens that are not themselves related to TAAs. Heterologous prime and OV/boost led to CD8+ T cell-dependent tumor cures using either SARS-CoV-2 Mem or Spike (S) proteins as vaccinating/tumor-focusing T cell targets, associated with epitope spreading against TAAs. We also show that CAR-T cells carry SARS-CoV-2 antigen-expressing vectors systemically to tumors even in pre-immune mice. Finally, S-specific CAR-T cells could be boosted in vivo with S protein vaccines to enhance anti-tumor activity and persistence. Thus, where high affinity anti-tumor T cells are not available, boosting preexisting infection- or vaccination-induced T cell populations within tumors using OV-mediated immunogen delivery provides a therapeutically valuable alternative.
    Keywords:  SARS-CoV-2; cancer immunotherapy; oncolytic viruses; single cycle adenovirus; tumor antigens; vaccines; vesicular stomatitis virus; virus T cell memory
    DOI:  https://doi.org/10.1016/j.ymthe.2025.08.023
  18. Antioxidants (Basel). 2025 Aug 18. pii: 1008. [Epub ahead of print]14(8):
      Intercellular mitochondrial transfer in the tumor microenvironment (TME) is a paradigm-shifting process that redefines cancer-T cell crosstalk. This review explores its dual nature as both a tumor immune evasion strategy and a promising therapeutic avenue. Crucially, oxidative stress acts as a key regulator, inducing tunneling nanotube (TNT) formation to facilitate this organelle exchange. Tumors exploit this by transferring dysfunctional, reactive oxygen species (ROS) generating mitochondria to T cells to induce senescence while simultaneously hijacking healthy mitochondria from T cells to empower their own metabolism. This directional exchange, quantified by computational tools like mitochondrial-enabled reconstruction of cellular interactions (MERCI), is linked to poor clinical outcomes. Transfer occurs via TNTs, extracellular vesicles, and direct contact. Conversely, the therapeutic transfer of healthy mitochondria from sources like mesenchymal stromal cells can revitalize exhausted T cells, improving chimeric antigen receptor T (CAR-T) cell efficacy. Clinical translation is guided by emerging biomarkers, including circulating mitochondrial DNA (mtDNA), mitochondrial haplogroups, and the tumor mitochondrial transfer (TMT) score. Harnessing this biological axis for next-generation immunotherapies requires overcoming challenges in transfer efficiency and standardization to effectively modulate the tumor redox landscape and immune response.
    Keywords:  MERCI methodology; T cell exhaustion; cancer metabolism; immune evasion; immunotherapy; mitochondrial transfer; oxidative stress; single-cell analysis; tumor microenvironment; tunneling nanotubes
    DOI:  https://doi.org/10.3390/antiox14081008
  19. Med Sci (Basel). 2025 Jul 28. pii: 100. [Epub ahead of print]13(3):
      Aging is associated with complex immune dysfunction that contributes to the onset and progression of the "geriatric giants", including frailty, sarcopenia, cognitive decline, falls, and incontinence. Central to these conditions is immunosenescence, marked by thymic involution, the loss of naïve T cells, T-cell exhaustion, impaired B-cell class switch recombination, and increased autoreactivity. Concurrently, innate immunity deteriorates due to macrophage, neutrophil, and NK cell dysfunction, while chronic low-grade inflammation-or "inflammaging"-amplifies systemic decline. Key molecular pathways such as NF-κB, mTOR, and the NLRP3 inflammasome mediate immune aging, interacting with oxidative stress, mitochondrial dysfunction, and epigenetic modifications. These processes not only impair infection control and vaccine responsiveness but also promote tissue degeneration and multimorbidity. This review explores emerging interventions-ranging from senolytics and immunonutrition to microbiome-targeted therapies and exercise-that may restore immune homeostasis and extend healthspan. Despite advances, challenges remain in translating immunological insights into clinical strategies tailored to older adults. Standardization in microbiome trials and safety optimization in senolytic therapies are critical next steps. Integrating geroscience into clinical care could help to mitigate the burden of aging-related diseases by targeting fundamental drivers of immune dysfunction.
    Keywords:  SASP; aging; frailty; geriatric giants; geriatric medicine; immunology; immunosenescence; inflammaging; sarcopenia
    DOI:  https://doi.org/10.3390/medsci13030100
  20. Front Immunol. 2025 ;16 1673414
      
    Keywords:  aging; cytokines; extracellular vesicles; immunity; mitochondria
    DOI:  https://doi.org/10.3389/fimmu.2025.1673414
  21. Gan To Kagaku Ryoho. 2025 Jul;52(7): 485-491
      The cancer-immunity cycle has been proposed, and immunotherapeutic approaches, such as vaccines using self-antigens and adjuvant, have been employed for a long time, but their therapeutic effects have been limited. However, recent studies have demonstrated that immune checkpoint inhibitors(ICIs)are able to achieve high therapeutic efficacy, in a variety of cancer types. Today, advances in multi-omics technologies, including single-cell RNA sequencing(scRNA-seq), spatial transcriptomics, and multicolor immunostaining technologies, have made it possible to analyze immune cell dynamics at the single-cell level in a greater detail. While CD8+ T cells play a central role in the antitumor immune response, recent findings have revealed the existence of various subsets within the CD8+ T cell population. During the research on T cell exhaustion, the in vivo dynamics of T progenitor exhausted cells(Tpex cells)/stem cell memory T cells(TSCM)have also been elucidated. Tpex/TSCM cells are present in tumor-draining lymph nodes and within tumors and have reported to be an important target for ICIs. Furthermore, interactions between CD4+ T cells, dendritic cells(DCs), B cells, and CD8+ T cells within the tumor microenvironment are crucial for the induction of cytotoxic CD8+ effector T cells. In human tumor tissues, cancer cells exhibit heterogeneous characteristics and the tumor microenvironment varies depending on cancer type, subtypes, and individual patients. To enhance the anti-tumor effects of CD8+ T cells in immunotherapy, it is essential to achieve a more precise understanding of the in vivo dynamics of CD8+ T cells in each patient and to develop strategies for their effective intervention. This knowledge will then be applied to the development of vaccine therapies, combination immunotherapies, and cellular immunotherapy.
  22. Cancer Cell. 2025 Aug 18. pii: S1535-6108(25)00329-0. [Epub ahead of print]
      The combined effects of aging and cancer on immune cells were investigated in young versus aged mice harboring B cell lymphoma, and in T cells from young and aged B cell lymphoma patients. These analyses revealed that lymphoma alone is sufficient to trigger transcriptional, epigenetic, and phenotypic alterations in young T cells that manifest in aged T cells. In contrast, aged T cells are largely resistant to lymphoma-induced changes. Pathway analyses revealed open chromatin regions and genes controlling iron homeostasis are induced by both lymphoma and aging, and lymphoma-experienced and aged T cells have increased iron pools and are resistant to ferroptosis. Furthermore, both aged and lymphoma-experienced T cells have defects in proteostasis. B cell lymphoma also accelerates aging of other tissues, as evidenced by elevated expression of Cdkn2a and Tnfa. Finally, some lymphoma-induced aging phenotypes are reversible whereas others are fixed, indicating opportunities for improving some cancer-associated aging comorbidities.
    Keywords:  B cell lymphoma; NK cell; T cell; aging; ferroptosis
    DOI:  https://doi.org/10.1016/j.ccell.2025.07.023
  23. Am J Transplant. 2025 Aug 25. pii: S1600-6135(25)02940-5. [Epub ahead of print]
      Cardiac allograft vasculopathy remains a major cause of late morbidity following heart transplantation. While accumulating evidence implicates innate macrophages in the inflammatory progression of CAV, the underlying mechanisms remain incompletely understood. In murine models of CAV, we identified proteolytic cleavage of MERTK, a key anti-inflammatory receptor on macrophages, as a contributing factor to CAV progression. In a model of CAV, MERTK deficiency accelerated allograft rejection and increased intimal leukocyte infiltration. In contrast, mice expressing a genetically cleavage-resistant form of MERTK (MertkCR/CR) exhibited prolonged graft survival, reduced intimal thickening, diminished immune cell infiltration, and decreased circulating effector T cells. Macrophages isolated from MertkCR/CR allografts had enhanced mitochondrial metabolism, which correlated with the production of anti-inflammatory cytokines including IL-10. Mechanistically, co-culture experiments demonstrated activated CD8+ T cells, and not CD4+ or naïve CD8+ T cells, induce MERTK cleavage on macrophages leading to reduced efferocytosis, increased glycolysis, and increased inflammatory cytokine expression. Together, our findings identify MERTK as a critical regulator of macrophages efferocytosis and metabolism in the context of cardiac transplantation. Our data suggest that MERTK activity protects against CAV progression and that activated T cells may promote allograft injury, in part, by driving MERTK proteolysis.
    Keywords:  Efferocytosis; Macrophage; Transplant; Vasculopathy
    DOI:  https://doi.org/10.1016/j.ajt.2025.08.026
  24. Semin Oncol. 2025 Aug 19. pii: S0093-7754(25)00090-9. [Epub ahead of print]52(5): 152398
      Short-chain fatty acids (SCFAs), acetate, propionate, and butyrate, are the microbial metabolites that have significant functions in host immune modulation, especially T lymphocyte function. Implication by recent evidence indicates SCFAs regulate T-cell growth, differentiation, metabolism, effector function, and apoptosis through histone deacetylase (HDAC) inhibition, G-protein-coupled receptor (GPCR) signaling, and metabolic reprogramming processes. Butyrate, for example, enhances regulatory T cell (Treg) and Interleukin 10 (IL-10)-producing T helper 1 (Th1) cell differentiation as well as context-dependent regulation on T helper 17 (Th17) cell development. SCFAs also impact cytotoxic CD8+ T cells through augmented production of IFN-γ and memory formation, which enhances antiviral and antitumor immunity. SCFAs reprogram T-cell metabolism through enhanced acetyl-CoA, mechanistic target of rapamycin (mTOR) signaling, and fatty acid oxidation (FAO), thus promoting the unique metabolic requirements of effector and memory T-cell subsets. In addition, SCFAs induce apoptosis of activated T cells through the Fas upregulation by inhibiting HDAC1. SCFA dysregulation plays a role in disease and autoimmune disorders like type 1 diabetes and rheumatoid arthritis, whereas therapeutic supplementation reduces inflammation and immune tolerance. SCFAs also amplify the antitumor effect of immune checkpoint inhibitors (eg, anti-programmed cell death protein 1 (anti-PD-1)) in cancer by driving CD8+ T-cell activation, infiltration, and Interferon gamma (IFNγ) production, partially through the transcriptional regulator Inhibitor of DNA binding 2 (ID2). Significantly, tissue- and disease-specific differential expression and functional implication of SCFA receptors (eg, GPR43, GPR41, GPR109A) emphasize the complexity of SCFA-mediated signaling. In conclusion, the current review emphasizes the multifunctional role of microbiota-derived SCFAs in T lymphocyte biology and their therapeutic potential in cancer, infection, and autoimmune diseases.
    Keywords:  Autoimmune diseases; Cancer; Immunomodulation; SCFAs; Th1; Th17; Tregs
    DOI:  https://doi.org/10.1016/j.seminoncol.2025.152398
  25. Front Immunol. 2025 ;16 1596686
      The senescence of immune cells has also emerged as a key hallmark of immunological dysregulation and chronic inflammation in autoimmunity. Senescent immune cells are irreversibly arrested in the cell cycle, exhibit antimetabolic characteristics, and secrete pro-inflammatory mediators, all together disrupting immune homeostasis. T cells, B cells, and innate immune subsets, acquire a senescence-associated secretory phenotype (SASP), which initiates tissue damage and sustains continuous inflammation in autoimmune diseases. The accumulation of senescent immune cells undermines immune surveillance, disrupts self-tolerance mechanisms, and enhances autoantibody production, all of which contribute to the pathogenesis of autoimmune diseases, including type 1 diabetes (T1D), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). Accumulating evidence reveals that metabolic stress, chronic DNA damage, and persistent antigenic exposure in inflammatory microenvironments induce immune cell senescence. Such senescent condition more aggressively promotes disease pathogenesis by compromising antigen presentation, disrupting cytokine signaling, and weakening the function of regulatory T cells (Tregs). Targets of senolytic drugs, SASP inhibitors, monoclonal antibodies (mAbs), and CAR T cell therapy currently have the potential to accelerate autoimmune pathology. These treatments would be directed specifically against the selective elimination or reprogramming of senescent cells to restore immune homeostasis. This review examines the mechanistic relationships between autoimmune development and immune cell senescence, as well as recent advancements in senescence-directed therapy. Understanding these pathways can provide new insights into autoimmune pathogenesis and inform future therapeutic approaches to immune cell aging.
    Keywords:  autoimmune disease; immune cell senescence; monoclonal antibody; senescence-associated secretory phenotype; senolytics
    DOI:  https://doi.org/10.3389/fimmu.2025.1596686
  26. Immunity. 2025 Aug 16. pii: S1074-7613(25)00331-0. [Epub ahead of print]
      Tissue-resident memory T cells (Trms) are essential for mucosal immunity. We postulated that their long-lived tissue residency and restricted effector function promoted HIV-1 persistence in the gut. We coupled single-cell DOGMA-seq and TREK-seq to capture chromatin accessibility, transcriptome, surface proteins, T cell receptors (TCRs), HIV-1 DNA, and HIV-1 RNA in gut CD4+ and CD8+ T cells from ten aviremic HIV-1+ individuals and five HIV- donors. BACH2, a transcriptional repressor that establishes long-lived memory in T cells, was a key transcription factor that shaped gut Trms into long-lived memory and restrained interferon-driven effector function. BACH2-ablation shifted long-lived central memory T cells to effector memory. HIV-1-infected cells were predominantly identified among BACH2high Trms, and HIV-1 preferentially infected and persisted in gut Trms in vitro. HIV-1-specific CD8+ T cells exhibited tissue residency and epigenetic scars of exhaustion, contributing to HIV-1 immune evasion in the gut. Overall, our findings indicate that HIV-1 persists in BACH2-shaped long-lived Trms.
    Keywords:  BACH2; HIV cure; HIV-1 reservoir; HIV-1-specific CD8(+) T cells; T cell clonal expansion; T cell homeostasis; gut; mucosal immunity; single-cell multi-omics; tissue-resident memory T cell
    DOI:  https://doi.org/10.1016/j.immuni.2025.07.022
  27. J Hepatol. 2025 Aug 22. pii: S0168-8278(25)02443-2. [Epub ahead of print]
      
    DOI:  https://doi.org/10.1016/j.jhep.2025.08.008
  28. Cancer Cell. 2025 Aug 02. pii: S1535-6108(25)00315-0. [Epub ahead of print]
      B cell lymphomas arise from mutations that disrupt normal germinal center B cell programs and promote a microenvironment that fosters aberrant proliferation and immune escape. In this issue of Cancer Cell, Hesterberg et al. show that lymphoma accelerates T cell aging by transcriptional and epigenetic reprogramming that mirrors physiological aging.
    DOI:  https://doi.org/10.1016/j.ccell.2025.07.009
  29. Antioxidants (Basel). 2025 Jul 25. pii: 911. [Epub ahead of print]14(8):
      Sarcopenia, the progressive loss of muscle mass, strength, and regenerative capacity with age, is driven by interconnected processes such as oxidative stress, chronic inflammation, mitochondrial dysfunction, and reduced activity of muscle stem cells. As the population ages, nutritional strategies that target these mechanisms are becoming increasingly important. This review focuses on nicotinamide (vitamin B3) and pyridoxine (vitamin B6), two essential micronutrients found in functional foods, which play complementary roles in redox regulation, immune balance, and muscle repair. Nicotinamide supports nicotinamide adenine dinucleotide (NAD+) metabolism, boosts mitochondrial function, and activates sirtuin pathways involved in autophagy and stem cell maintenance. Pyridoxine, via its active form pyridoxal 5'-phosphate (PLP), is key to amino acid metabolism, antioxidant defense, and the regulation of inflammatory cytokines. We summarize how these vitamins influence major molecular pathways such as Sirtuin1 (SIRT1), protein kinase B (AKT)/mechanistic target of rapamycin (mTOR), Nuclear factor-κB (NF-κB), and Nrf2, contributing to improved myogenic differentiation and protection of the aging muscle environment. We also highlight emerging preclinical and clinical data, including studies suggesting possible synergy between B3 and B6. Finally, we discuss how biomarkers such as PLP, nicotinamide mononucleotide (NMN), and C-reactive protein (CRP) may support the development of personalized nutrition strategies using these vitamins. Safe, accessible, and mechanistically grounded, nicotinamide and pyridoxine offer promising tools for sarcopenia prevention and healthy aging.
    Keywords:  inflammaging; muscle regeneration; muscle stem cells; nicotinamide; nicotinamide adenine dinucleotide (NAD+) metabolism; nutritional intervention; pyridoxine; sarcopenia
    DOI:  https://doi.org/10.3390/antiox14080911
  30. Cell Rep Med. 2025 Aug 20. pii: S2666-3791(25)00384-2. [Epub ahead of print] 102311
      Despite antiretroviral therapy, HIV-1 mainly persists in memory CD4+ T cells in people living with HIV-1. Most long-lived viral reservoir cells are infected by the virus near the time of therapy initiation. A better understanding of the early events in viral reservoir seeding presents opportunities for preventing latent reservoir formation. Here, we demonstrate that CD4+ T cells expressing CCR5, permissive to HIV-1 infection, are effector or terminally differentiated cells. BTB domain and CNC homolog 2 (BACH2) is expressed by a small subset of CCR5+ cells and reverses their terminal differentiation. BACH2-mediated memory differentiation is impeded due to heightened inflammation before treatment initiation. Mice with a BACH2-knockout human immune system have a reduced frequency of HIV-1 reservoir cells and do not experience virus rebound after treatment discontinuation. Our study reveals that BACH2 is essential to the seeding and establishment of long-lived HIV-1 reservoir in memory CD4+ T cells.
    Keywords:  ART; BACH2; CCR5; CD4(+) T cells; HIV-1; humanized mice; memory differentiation; terminal differentiation; viral reservoirs
    DOI:  https://doi.org/10.1016/j.xcrm.2025.102311
  31. NPJ Aging. 2025 Aug 20. 11(1): 76
      Lifespan extension has not prevented age-related decline. We propose that diet acts as a molecular modulator of aging, influencing inflammation, the microbiome, and systemic resilience. Biological age markers and AI-powered multi-omics reveal actionable dietary targets, including food-derived signals and Nutrition Dark Matter. We highlight precision nutrition and the EIT Food Healthy Aging Think & Do Tank as pathways to align science, policy, and practice for healthy aging.
    DOI:  https://doi.org/10.1038/s41514-025-00266-5
  32. Trends Immunol. 2025 Aug 26. pii: S1471-4906(25)00200-5. [Epub ahead of print]
      Gut dysbiosis and intestinal inflammation may contribute to neurological disorders through the gut-brain axis. A recent report by White et al. uncovered that intestinal inflammation triggers the migration of microbiota-specific CD4+ T cells to the brain, where they drive neuroinflammatory responses via IL-23R/GM-CSF.
    Keywords:  CD4(+) T cell; gut inflammation; microbiota; molecular mimicry; neuroinflammation
    DOI:  https://doi.org/10.1016/j.it.2025.08.002
  33. JCI Insight. 2025 Aug 26. pii: e194570. [Epub ahead of print]
      BK virus nephropathy is a severe, graft-threatening complication of kidney transplantation that requires an effective T cell response. It typically emerges in the kidney medulla. Elevated osmolyte concentrations that dynamically respond to loop diuretic therapy characterize this environment. BK-viremia development in kidney graft recipients negatively correlated with loop diuretic therapy. The association remained significant in multivariable and propensity score matched analyses. Kidney function was better preserved and CD8+ T cell abundance higher in loop diuretic-exposed allografts. CD8+ T cell densities in healthy human and murine kidney medulla were lower than in cortex and increased upon loop diuretic therapy in mice. As a potential underlying mechanism, kidney medullary NaCl and urea concentrations decreased primary human CD8+ T cell numbers in vitro by induction of cell death and limitation of proliferation, respectively. Both osmolytes downregulated interferon-related gene expression. NaCl induced p53-dependent apoptosis and upregulated Na+-transporter SLC38A2, which promoted caspase 3 activation. Both decreased T cell response and cytokine secretion in response to viral peptide and allogenic tubular epithelial cell killing, components of anti-BKV response in the kidney allograft. Our results propose osmolyte-mediated mitigation of CD8+ T cell function as a what we believe to be novel mechanism that impairs immune response to BK virus, therapeutic potential of which is testable.
    Keywords:  Adaptive immunity; Epithelial transport of ions and water; Immunology; Nephrology; Organ transplantation
    DOI:  https://doi.org/10.1172/jci.insight.194570
  34. J Immunol. 2025 Aug 25. pii: vkaf194. [Epub ahead of print]
      As a result of the growing use of nuclear energy and radiation in medical interventions within the last decade, the potential for radiation exposure among the general public has increased. Exposure to high doses of radiation severely impairs the immune system, including CD8 T cells. While the effects on the naïve and primary memory (1M) CD8 T cell pools have been partially characterized, the effect of radiation exposure on CD8 T cell memory generated after repeated antigen (Ag) exposures has not. Here, we utilized a series of adoptive transfers to generate chimeric mice containing Thy1 distinct 1M and quaternary memory (4M) P14 CD8 T cells within the same host. We found that 1M and 4M were equally susceptible to radiation-induced cell death early after irradiation. In addition, both cell types showed diminished Ag-driven cytokine production and ability to proliferate upon cognate Ag restimulation in vivo. Despite evidence that 1M and 4M attempt cell cycling in response to the lymphopenic environment, neither group numerically recovers with time. Irradiated 1M and 4M showed decreased expression of key homeostatic cytokine receptors, though expression levels of CD122/CD127 are further diminished in 4M. This, in turn, leads to changes in the composition of the memory CD8 T cell compartment in which the representation of memory CD8 T cells with history of repeated Ag stimulations is further reduced. Thus, numerical and functional recovery of memory CD8 T cells generated after repeated infections/vaccinations in radiation survivors is severely impaired, potentially leaving the host with increased susceptibility to reinfection(s).
    Keywords:  irradiation; memory CD8 T cells; repeated antigen stimulations
    DOI:  https://doi.org/10.1093/jimmun/vkaf194
  35. FASEB J. 2025 Aug 31. 39(16): e70964
      With the growing demand for adult orthodontic treatment, age-related changes in clinical outcomes have emerged as significant challenges. However, effective strategies to improve outcomes in aging patients remain limited. Periodontal ligament stem cells (PDLSCs), a mechanosensitive subpopulation of mesenchymal stem cells, play a significant role in bone remodeling during orthodontic tooth movement (OTM) and are increasingly recognized as key contributors to the decline in orthodontic responsiveness with age. This review highlights the multifaceted role of PDLSCs in OTM, encompassing mechanosensation, mechanotransduction, and subsequent bone remodeling. It further examines how aging impairs PDLSC biology and potentially contributes to reduced orthodontic responsiveness in older individuals. Key aging-related mechanisms are described, including increased oxidative stress, disrupted mitochondrial homeostasis, impaired autophagy, loss of proteostasis, and epigenetic modifications. Dysregulation of intracellular signaling pathways further underscores the complexity of age-related functional decline. Based on these insights, emerging strategies for rescuing aged PDLSCs are summarized, offering a theoretical foundation for developing targeted interventions to enhance orthodontic outcomes in the aging population.
    Keywords:  age‐related changes; mitochondrial dysfunction; orthodontic; periodontal ligament stem cell; stem cell aging; stem cell rescue
    DOI:  https://doi.org/10.1096/fj.202501731R