bims-imseme 2025-08-17 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2025–08–17
33 papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Mitochondrial Metabolism in T-Cell Exhaustion.
USP30 inhibition augments mitophagy to prevent T cell exhaustion.
The high (I)COSt of costimulation for exhausted T cells.
Chromatin repression by PRC2 results in reduced gene expression driving key features of CD8 T cell exhaustion.
Succinate preserves CD8+ T cell fitness to augment antitumor immunity.
Metabolic regulation of immunological aging.
Inflammaging in aged tissues drives remodeling of the CD8 + T cell compartment.
A STUB1-CHIC2 complex inhibits CD8+ T cells to restrain tumor immunity.
Prdm12 governs an epigenetic checkpoint linking neuroimmune cross-talk to CD8+ T cell exhaustion-suppressed antitumor immunity.
Mechanical signaling via β2 integrin decouples T cell proliferation and differentiation for generating stem cell-like CAR T cells.
Aging reshapes the adaptive immune system from healer to saboteur.
Mitochondrial Dysfunction in Aging and Age-related Disorders.
H2A.Z primes an epigenetic landscape for memory CD8+ T cell recall response.
Sustained immune youth risks autoimmune disease in the aging host.
Exercise Duration Modulates Cortisol Release and Chronic Cortisol Exposure Jeopardises T Cell Effector Functions.
Metabolic Regulation of Cardiovascular Aging.
Modeling Combination Therapies and T Cell Exhaustion Dynamics in the Tumor Under Immune Checkpoint Blockade.
DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps.
Therapeutic CD8+ T cell tissue retention and immunomodulation during ART interruption fail to prevent SIV rebound.
The immune system offers a window into aging.
The liver metabolizes dietary galactose to fuel antitumour T cell immunity.
Expanding the cytokine receptor alphabet reprograms T cells into diverse states.
Targeting ferroptosis restores the antiviral activity of CD8+ T cells during chronic HBV infection.
Recent advances in exercise immunometabolism: Immune cell bioenergetics, muscle-immune cell interactions, and potential dietary adjuvants.
SIRPγ modulates effector differentiation of human CD8 T Cells under suboptimal TCR stimulation: implications for immune homeostasis and autoimmunity.
Species-specific serine metabolism differentially controls natural killer cell functions.
CD1d-Restricted NKT Cells Promote Central Memory CD8+ T Cell Formation via an IL-15-pSTAT5-Eomes Axis in a Pathogen-Exposed Environment.
Hyperactive PLCG1 induces cell-autonomous and bystander T cell activation and drug resistance.
Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice.
Pik3ip1/TrIP Regulation of PI3K Restricts CD8 T Cell Anti-Tumor Immunity.
Asparaginase Enhances CAR-T Cell Antitumor Immunity by Asparagine Metabolic Reprogramming and Induction of Central Memory Phenotype in ALL.
CD31 regulates metabolic switch in Treg migration attenuates rheumatoid arthritis.
Understanding and improving vaccine efficacy in older adults.

Int J Mol Sci. 2025 Jul 31. pii: 7400. [Epub ahead of print]26(15):

Mitochondrial Metabolism in T-Cell Exhaustion.

Fei Li, Yu Feng, Zesheng Yin, Yahong Wang.

  T cells play a vital role in resisting pathogen invasion and maintaining immune homeostasis. However, T cells gradually become exhausted under chronic antigenic stimulation, and this exhaustion is closely related to mitochondrial dysfunction in T cells. Mitochondria play a crucial role in the metabolic reprogramming of T cells to achieve the desired immune response. Here, we compiled the latest research on how mitochondrial metabolism determines T cell function and differentiation, with the mechanisms mainly including mitochondrial biogenesis, fission, fusion, mitophagy, and mitochondrial transfer. In addition, the alterations in mitochondrial metabolism in T-cell exhaustion were also reviewed. Furthermore, we discussed intervention strategies targeting mitochondrial metabolism to reverse T cell exhaustion in detail, including inducing PGC-1α expression, alleviating reactive oxygen species (ROS) production or hypoxia, enhancing ATP production, and utilizing mitochondrial transfer. Targeting mitochondrial metabolism in exhausted T cells may achieve the goal of reversing and preventing T cell exhaustion.

Keywords:  T-cell exhaustion; metabolic reprogramming; metabolism; mitochondria; mitochondrial dynamics

DOI:  https://doi.org/10.3390/ijms26157400
Sci Adv. 2025 Aug 15. 11(33): eadv6902

USP30 inhibition augments mitophagy to prevent T cell exhaustion.

Ruohan Zhang, Fengxia Gao, Jianying Li, Jiacheng Jin, Kangxuan Chen, Samhita Chaudhuri, Zhiwei Liao, Tong Xiao, Yang Xu, Haitao Wen, Kai He, Zihai Li, Gang Xin, Nuo Sun.

The exhaustion of tumor-infiltrating CD8+ T cells poses a substantial challenge in cancer immunotherapy, with mitochondrial health essential for sustaining T cell functionality. Mitophagy, a critical process for mitochondrial quality control, is severely impaired in exhausted CD8+ T cells, yet the underlying mechanisms remain unclear. We identified ubiquitin-specific protease 30 (USP30), a mitochondrial deubiquitinase that inhibits mitophagy, as a key factor up-regulated in exhausted CD8+ T cells. Notably, prolonged antigen stimulation triggers the T cell receptor and nuclear factor of activated T cell 1 signaling, which drives the transcriptional up-regulation of USP30. Excitingly, our interventions targeting USP30 through genetic deletion or pharmacological inhibition effectively restored mitophagy, improved mitochondrial fitness, and rejuvenated CD8+ T cell effector functions. These interventions reinvigorated antitumor responses and markedly suppressed tumor growth. Our findings establish USP30 as a critical regulator of mitophagy and a promising therapeutic target for reversing T cell exhaustion and enhancing the efficacy of cancer immunotherapy.

DOI: https://doi.org/10.1126/sciadv.adv6902
Immunity. 2025 Aug 12. pii: S1074-7613(25)00319-X. [Epub ahead of print]58(8): 1882-1884

The high (I)COSt of costimulation for exhausted T cells.

Maria N de Menezes, Ian A Parish.

ICOS agonists are being investigated for cancer immunotherapy based on the idea that they will reinvigorate exhausted CD8+ T cell anti-cancer immunity. Humblin et al. unexpectedly find the opposite-that CD8+ T cell-intrinsic ICOS expression restrains rather than promotes exhausted CD8+ T cell function in both chronic viral infection and tumor models.

DOI: https://doi.org/10.1016/j.immuni.2025.07.010
J Immunol. 2025 Aug 07. pii: vkaf188. [Epub ahead of print]

Chromatin repression by PRC2 results in reduced gene expression driving key features of CD8 T cell exhaustion.

Parisa Samareh, Paula Agudelo-Garcia, Zhen Zhang, Michael Gilbert, Mariel Mendoza, Hua Huang, Jennifer E Wu, Amy E Baxter, Zeyu Chen, Kate Alexander, E John Wherry, Charly R Good, Shelley L Berger.

  Exhausted CD8 T cells result from chronic antigen stimulation and have reduced ability to clear disease. The epigenetic regulation of the dysfunctional phenotype of exhausted CD8 T cells is a promising avenue for therapies aimed at reversing or preventing CD8 T cell exhaustion. Here, utilizing in vitro and in vivo models, we show global increase of the repressive histone modification H3K27me3 in CD8 T cell exhaustion and increased gene expression of the EZH2 form of the PRC2 complex, which is responsible for H3K27me3 deposition. H3K27me3 correlated with decreased gene expression and localized to naive/memory T cell genes in CD8 T cell exhaustion. PRC2 inhibition increased expression of the naive/memory genes while reducing expression of key exhaustion genes. Further, we identified potential enhancers and transcription factors predicted to promote expression of the PRC2 subunits. Our study highlights the importance of the repressive epigenetic landscape of exhausted CD8 T cells as well as a novel role for PRC2 in T cell biology.

Keywords:  cancer; chromatin; exhaustion; infection; repression

DOI:  https://doi.org/10.1093/jimmun/vkaf188
Immunity. 2025 Aug 09. pii: S1074-7613(25)00326-7. [Epub ahead of print]

Succinate preserves CD8+ T cell fitness to augment antitumor immunity.

Kaili Ma, Hongcheng Cheng, Lin Wang, Han Xiao, Fenghua Liu, Yu Yang, Zhen Xiao, Kun Tang, Shicheng Li, Gang Wang, Minmin Ge, Jiajia Wang, Xiaowei Liu, Hai-Xi Sun, Ziyi Luo, Zhimin Gu, Ping-Chih Ho, Guideng Li, Lianjun Zhang.

  Succinate, a tricarboxylic acid cycle intermediate, accumulates in tumors with succinate dehydrogenase (SDH) mutations. Although succinate is recognized for modulating CD8+ T cell cytotoxicity, its impact on T cell differentiation remains poorly understood. Here, we reveal that succinate accumulation in tumors lacking the SDH subunit B (SDHB) enhanced tumor-reactive CD8+ T cell-mediated immune responses. Sustained succinate exposure promoted CD8+ T cell survival and facilitated the generation and maintenance of stem-like subpopulations. Mechanistically, succinate enhanced mitochondrial fitness through Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3)-mediated mitophagy and also promoted stemness-associated gene expression via epigenetic modulation. Succinate-conditioned CD8+ T cells displayed superior long-term persistence and tumor control capacity. Moreover, succinate enrichment signature correlates with favorable clinical outcomes in certain melanoma and gastric cancer patients receiving immune checkpoint blockade therapy. These findings reveal how succinate preserves T cell stemness and highlight the therapeutic potential of succinate supplementation for enhancing T cell immunotherapy efficacy.

Keywords:  SDHB-deficient tumor; T cell stemness; TCF-1; antitumor immune response; epigenetic reprogramming; exhaustion; immune checkpoint blockade; mitochondrial fitness; mitophagy; succinate

DOI:  https://doi.org/10.1016/j.immuni.2025.07.017
Nat Aging. 2025 Aug;5(8): 1425-1440

Metabolic regulation of immunological aging.

Hee-Hoon Kim, Vishwa Deep Dixit.

All biological activities require energy through the intake and generation of metabolites. After reproductive age, altered metabolism, together with cellular and molecular perturbations in the immune system, are linked to organismal functional decline. Unresolved chronic inflammation originating from innate immune cells and loss of naive T cells with restriction of T cell receptor repertoire diversity emanating from age-related thymic involution are some of the mechanisms that limit healthspan and even lifespan. Here, we provide an overview of the hallmarks of immunological aging and synthesize how the immune system, coupled to cellular and organismal metabolism, controls disease susceptibility. Furthermore, we highlight the potential unifying immunometabolic mechanisms of various genetic, pharmacological and dietary interventions that may underlie lifespan-healthspan extension. Given that immune and metabolic systems are modifiable and targetable, understanding the role of myriads of organ-resident immune cells and the underlying metabolic mechanisms that cause dysfunction can have transformational potential for the health of older adults.

DOI: https://doi.org/10.1038/s43587-025-00921-2
bioRxiv. 2025 Jul 17. pii: 2025.07.11.664388. [Epub ahead of print]

Inflammaging in aged tissues drives remodeling of the CD8 + T cell compartment.

Irina Shchukina, Carlos J Rodriguez-Hernandez, Heather S Ruiz, Maksim Kleverov, Rachel L Mintz, Katsutaka Mineura, Subhadra C Gunawardana, Sunnie Hsiung, Veronika Vachova, Jan Kossl, Denis A Mogilenko, Christopher G Huckstep, Barbora Vander Wielen, David W Piston, Takeshi Egawa, Daniel Kreisel, Gwendalyn J Randolph, Maxim N Artyomov.

Aging profoundly reshapes the immune cell landscape, with particularly strong effects on CD8 + T cells, including a marked decline in naïve cells and the emergence of age-associated GZMK + CD8 + T cells (T AA cells). Although T AA cells make up a significant fraction of the aged CD8 + T cell compartment, the pathway underlying their development remains unknown. In this study, we demonstrate that T AA cell development is cell-extrinsic and requires antigen exposure within aged non-lymphoid tissues. Using a novel TNF Δ69AU/+ mouse model, we show that systemic low-grade inflammation, characteristic of inflammaging, accelerates CD8 + T cell aging and promotes early accumulation of T AA cells. Through detailed analysis of T AA cell heterogeneity, we identified a progenitor subpopulation enriched in the aged adipose tissue. Using heterochronic transplantation, we show that adipose tissue acts as a functional niche, supporting progenitor maintenance and driving the conversion of young CD8 + T cells into the aged phenotype. Taken together, our findings reveal how aging of non-lymphoid tissues orchestrates the reorganization of the CD8 + T cell compartment and highlight adipose tissue as a promising target for therapeutic strategies aimed at modulating immune aging.

DOI: https://doi.org/10.1101/2025.07.11.664388
Nat Immunol. 2025 Aug 12.

A STUB1-CHIC2 complex inhibits CD8+ T cells to restrain tumor immunity.

Martin W LaFleur, Lauren E Milling, Priyamvada Prathima, Vivian Li, Ashlyn M Lemmen, Ivy S L Streeter, Paul K S Heisig, Nicole M Derosia, Elizabeth Riffo, Haonan Xu, Thao H Nguyen, Aashiya Kolengaden, Samuel C Markson, John G Doench, Arlene H Sharpe.

In vivo CRISPR screens in CD8+ T cells have previously uncovered targets for cancer immunotherapy; however, a minority of the genome has been individually annotated, suggesting that additional regulators remain to be discovered. Here we assessed 899 genes in CD8+ T cells responding to murine melanoma and identified the E3 ubiquitin ligase STUB1 as a new negative regulator of anti-tumor CD8+ T cell function. We demonstrated that Stub1 knockout CD8+ T cells effectively control tumor growth across multiple murine models. Mechanistically, STUB1 interacts with the adapter protein CHIC2 to regulate cytokine receptor expression in mouse and human CD8+ T cells. Among the regulated cytokine receptors, interleukin-27 receptor α is essential for tumor growth control mediated by Stub1/Chic2 knockout CD8+ T cells. Together, these findings establish the STUB1-CHIC2 complex as a regulator of cytokine receptor expression in CD8+ T cells and provide rationale for inhibiting this pathway to enhance CD8+ T cell-mediated anti-tumor immunity.

DOI: https://doi.org/10.1038/s41590-025-02231-6
Sci Adv. 2025 Aug 15. 11(33): eadx9221

Prdm12 governs an epigenetic checkpoint linking neuroimmune cross-talk to CD8+ T cell exhaustion-suppressed antitumor immunity.

Guolong Liu, Xiaoling Tian, Qiudao Wang, Saijuan Xu, Yanhong Jiang, Ying Gao, Yuxuan Wu.

CD8+ T play essential roles in antitumor immune responses. However, immunotherapy has limited clinical efficacy in many solid tumors. Here, we performed an epigenetic-wide CRISPR-Cas9 screen in CD8+ T cells directly under cancer immunotherapy setting and found that Prdm12 is a transcriptional repressor implicated in nociceptive neuron development but uncharacterized within immunological contexts. Prdm12 deletion markedly enhanced in vivo tumor clearance of mouse CD8+ T cells and promoted activation, effector differentiation marker expression, and cytokine secretion in both murine and human CD8+ T cells in vitro. Mechanistically, Prdm12 deficiency augmented effector transcriptional programs while inhibiting exhaustion of CGRP-RAMP1 neuroimmune axis facilitation. Additionally, Prdm12 ablation remodeled the chromatin accessibility landscape, with H3K9me3 deposition at loci regulating T cell differentiation (Trib1 and Sgk1) and exhaustion (Rgs1 and Nr4a2). These results together reveal a negative regulatory mechanism for CD8+ T cells and advance our understanding of cancer immunotherapy by linking neurobiological signaling to immune regulation.

DOI: https://doi.org/10.1126/sciadv.adx9221
Immunity. 2025 Aug 05. pii: S1074-7613(25)00327-9. [Epub ahead of print]

Mechanical signaling via β2 integrin decouples T cell proliferation and differentiation for generating stem cell-like CAR T cells.

Jiadi Lv, Tian Si, Dianheng Wang, Chaoqi Zhang, Yabo Zhou, Jin Yu, Yishen Jiang, Dongxiao Wu, Li Zhou, Zhenfeng Wang, Nannan Zhou, Jie Chen, Keke Wei, Huafeng Zhang, Jingwei Ma, Ke Tang, Xuetao Cao, Bo Huang.

  Downstream of T cell receptor (TCR) signaling, proliferation and differentiation programs are thought to be linked to maintain T cell homeostasis. This biology, however, also leads to the in vitro generation of suboptimal chimeric antigen receptor (CAR) T cells. Here, we show that proliferation and differentiation programs can be decoupled by fibrin matrix-based mechanical signaling, leading to abundant generation of undifferentiated stem cell-like CAR (stem-CAR) T cells. These stem-CAR T cells expressed NANOG, SOX2, and TCF1, exhibited persistent cytolysis in tumor cells in vitro, and achieved optimal efficacy in solid tumor models of breast, pancreatic, and brain cancer in vivo. Mechanistically, the fibrin matrix activated β2 integrin to recruit 14-3-3ζ, leading to Yes-associated protein (YAP) phosphorylation and inactivation. Consequently, YAP inactivation derepressed the transcription factor MafG. MafG then transactivated stemness genes, thereby generating stem-CAR T cells. These findings suggest a mechanical approach to manufacturing stem-CAR T cells, potentially improving CAR T cell therapeutic efficacy for cancer treatment.

Keywords:  CAR T cells; mechanical signaling; retrodifferentiation; solid tumors; stem cell-like T cells

DOI:  https://doi.org/10.1016/j.immuni.2025.07.018
Nat Aging. 2025 Aug;5(8): 1393-1403

Aging reshapes the adaptive immune system from healer to saboteur.

Sandra Delgado-Pulido, Matthew J Yousefzadeh, Maria Mittelbrunn.

The classical role of adaptive immunity as a protector against external threats has expanded to include its functions in cancer surveillance, tissue repair and regeneration, and, more recently, it has emerged as a regulator of the aging process. In this Perspective, we discuss the mechanisms by which the deterioration of adaptive immunity contributes to inflammaging, cellular senescence and age-associated pathologies. We propose that age-related changes in lymphocytes contribute to aging through two distinct mechanisms. First, adaptive immune function worsens with age, impairing immunosurveillance of damaged or senescent cells and diminishing tissue regenerative potential, thereby indirectly disrupting tissue homeostasis. This disruption is particularly important in the gut, where maintaining tissue and microbiota homeostasis is crucial for overall health during aging. Second, adaptive immune cells often acquire pro-inflammatory and autoaggressive phenotypes with age, directly driving tissue damage, promoting senescence and exacerbating inflammaging. Finally, we explore the therapeutic potential of strategies aimed at enhancing the protective functions of lymphocytes or modulating their pathogenic phenotypes to promote healthy aging.

DOI: https://doi.org/10.1038/s43587-025-00906-1
Aging Dis. 2025 Jul 31. 16(5): 2495-2497

Mitochondrial Dysfunction in Aging and Age-related Disorders.

Aida Adlimoghaddam.

Mitochondrial dysfunction is increasingly recognized as a unifying mechanism underlying aging and a wide range of age-related diseases. This special issue brings together recent advances that elucidate how impaired mitochondrial function contributes to neurodegenerative, cardiovascular, and metabolic disorders. The featured articles highlight molecular pathways of mitochondrial decline, its systemic consequences, and potential interventions aimed at restoring mitochondrial health. Collectively, these studies reinforce the concept that targeting mitochondrial integrity holds significant promise for promoting healthy aging and preventing chronic disease.

DOI: https://doi.org/10.14336/AD.2025.10731
Nat Commun. 2025 Aug 15. 16(1): 7625

H2A.Z primes an epigenetic landscape for memory CD8+ T cell recall response.

Wei Liang, Jiyu Ding, Qian Chai, Mengjie Lv, Shuting Zheng, Xiangxiang Cao, Zhimin Wang, Xiaoling Ying, Wenqi Wu, Guohong Li, Mingzhao Zhu.

The rapid recall ability is a hallmark of memory CD8+ T cells, but the underlying mechanisms remain incompletely understood. Here we find that histone variant H2A.Z is expressed at higher levels in memory CD8+ T cells than in naïve cells. Furthermore, in memory CD8+ T cells H2A.Z is deposited at the promoters and enhancers, particularly super enhancers, of those genes involved in recall responses, while H2A.Z deficiency in memory CD8+ T cells inhibits recall responses in vitro and in vivo. Mechanistically, multi-omics analyses show that H2A.Z maintains a poised epigenetic landscape on those recall response genes to potentiate a rapid transcription activation. Accordingly, H2A.Z deposition on these genes is induced by TCR/CD28 signals, and is cooperated by IL-7/IL-15 signals. Together, our data suggest that H2A.Z may orchestrate a specific epigenetic landscape during memory T cell differentiation to facilitate a rapid recall response.

DOI: https://doi.org/10.1038/s41467-025-62976-4
Nat Aging. 2025 Aug;5(8): 1404-1414

Sustained immune youth risks autoimmune disease in the aging host.

Cornelia M Weyand, Jörg J Goronzy.

Immune responses underlying autoimmune diseases follow the same principles that protect individuals from infection and malignancies. However, while protective immunity wanes with progressive age, the risk for autoimmune disease steadily increases; incidence rates for many autoimmune diseases peak in later life. Here, we discuss whether aging predisposes to autoimmunity, arguing that disease progression in the autoimmune vasculitis giant cell arteritis is driven by age-inappropriate sustenance of immune competence. Stem-like memory CD4+ T cells (TSCM) that reside near the vasculitic lesions provide a continuous supply of pathogenic effector T cells. Antigen-presenting cells lacking inhibitory ligands further impede peripheral tolerance mechanisms. In the context of aging-associated accumulation of neoantigens, this incessant immune competence sets the stage for unopposed autoimmunity. We propose that sustained immune youthfulness can be detrimental to the aging host, while immune aging may be a beneficial adaptation to balance reactivity to self-antigens and non-self-antigens and thus protect from autoimmunity in aging.

DOI: https://doi.org/10.1038/s43587-025-00919-w
Immunology. 2025 Aug 12.

Exercise Duration Modulates Cortisol Release and Chronic Cortisol Exposure Jeopardises T Cell Effector Functions.

Thy Viet Luu, Line Fleischer Hach, Tina Seremet, Katharina Leuchte, Per Thor Straten, Gitte Holmen Olofsson.

  Psychological stress has been linked to increased incidence and mortality of cancer. During stress, cortisol is released into circulation and regulates cellular processes including immune activity by acting on glucocorticoid receptors (GCRs) expressed by target cells. Chronic stress-induced cortisol has been suggested to promote tumour progression and compromise the efficacy of cancer treatments. Conversely, cortisol is also transiently secreted during exercise. Although exercise has been suggested to have beneficial effects against cancer, the impact of exercise-elevated cortisol on immune cell functions remains poorly understood. Here we studied the dynamics of cortisol secretion following exercise and how cortisol affects effector functions of T cells in the context of acute versus chronic stress. We show that 40 min of acute, high-intensity exercise in healthy adults significantly increased stable circulating cortisol levels whereas a 5-min sprint failed to. Acute exposure to cortisol for 4 h showed no negative effects on the proliferation, cytokine release, or killing activity of human CD3+ T cells. In contrast, chronic cortisol dampened these T cell effector functions. Furthermore, chronic cortisol exposure induced the proliferation of several cancer cell lines. Our findings highlight the opposing effects of cortisol during acute stress, such as exercise, compared to chronic stress, on cancer cells and T cells. This suggests an important potential in targeting cortisol signalling to enhance cancer immunotherapy.

Keywords:  T cell; cancer; neuroimmunology; regulation/suppression

DOI:  https://doi.org/10.1111/imm.70028
Curr Cardiol Rep. 2025 Aug 15. 27(1): 128

Metabolic Regulation of Cardiovascular Aging.

Michael Gao, Toren Finkel.

   PURPOSE OF REVIEW: Metabolic changes can play a critical role in the structural and functional decline of the aging cardiovascular system. In this review, we examine how key metabolic pathways and regulatory mechanisms influence cardiovascular aging, highlighting recent studies into metabolic flexibility, mitochondrial function, nutrient sensing, and energy utilization in the aging heart. Potential metabolic-based interventions to mitigate cardiac aging are also discussed.
RECENT FINDINGS: Various metabolic changes have been observed in the aging heart. Impaired metabolic flexibility, as seen by reduced fatty acid oxidation with an increased reliance on glucose, is observed. Mitochondrial dysfunction and increased oxidative stress in aged cardiomyocytes may lead to energy deficits, contributing to myocardial fibrosis and diastolic dysfunction. Accelerated cardiovascular aging is also connected to the dysregulation of nutrient-sensing pathways- such as AMP-activated protein kinase (AMPK), sirtuins, and the mechanistic target of rapamycin (mTOR). Enhancing the age-dependent decline in autophagy and mitophagy, which clears damaged organelles, appears to preserve cardiac function in aging. Recent studies have shown that interventions such as caloric restriction, exercise, and metformin can favorably remodel cardiac metabolism and delay age-related cardiac deterioration. Metabolic changes, including energy substrate shifts, mitochondrial oxidative stress, and impaired nutrient signaling, play a direct role in cardiovascular aging. Targeting these metabolic factors and pathways holds promise for alleviating age-associated cardiac dysfunction. Recent studies focusing on lifestyle or pharmacologic means of metabolic modulation provide and outline for the promotion of healthy cardiovascular aging, thereby reducing the burden of cardiovascular disease in the growing aging population.

Keywords:  Autophagy; Cardiovascular aging; Metabolic flexibility; Metabolism; Mitochondrial dysfunction; Nutrient sensing

DOI:  https://doi.org/10.1007/s11886-025-02279-8
Bull Math Biol. 2025 Aug 11. 87(9): 128

Modeling Combination Therapies and T Cell Exhaustion Dynamics in the Tumor Under Immune Checkpoint Blockade.

Xiulan Lai, Teng Yu.

Chronic antigen exposure in the tumor microenvironment drives CD 8+ T cell exhaustion, marked by increased inhibitory receptors and diminished effector functions. Immune checkpoint blockade seeks to prevent or reverse exhaustion, but its success relies on the pre-existing state of tumor-infiltrating T cells. To investigate this, we developed a mathematical model examining: (1) how T cell exhaustion disrupts tumor-immune equilibrium, (2) anti-PD-L1 efficacy across exhaustion states, and (3) efficacy of next-generation therapies (e.g., IFN α -anti-PD-L1, PD1-IL2v). Stability analysis and simulations reveal that tumor PD-L1 expression critically influences immune dynamics, particularly the bistability of tumor-free and tumorous states. High PD-1 expression and exhaustion rates correlate with growth of tumor and impaired expansion of less-exhausted CD 8+ T cells. While anti-PD-L1 efficacy depends on baseline exhaustion, severe exhaustion enables immune escape. Next-generation therapies enhancing cytotoxicity and sustaining less-exhausted T cell populations show improved tumor control, suggesting combination strategies may overcome resistance.

DOI: https://doi.org/10.1007/s11538-025-01507-0
Cancer Cell. 2025 Jul 30. pii: S1535-6108(25)00320-4. [Epub ahead of print]

DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(L)1 therapy efficacy by degrading neutrophil extracellular traps.

Degao Chen, Zheng Jin, Han Chu, Yucui Wu, Yangping Bian, Ting Yuan, Hao Lv, Qiuyu Xia, Lei Wang, Qian Chu, Quanxing Liu, Dong Zhou, Wenfeng Fang, Xiaoming Cheng, Haoran Zha, Haixia Long, Li Zhang, Jigang Dai, Yisong Y Wan, Qi-Jing Li, Qingzhu Jia, Xindong Liu, Bo Zhu.

  CD8+ T cell exclusion and dysfunction in the tumor microenvironment (TME) are among the most challenging obstacles for anti-PD-(L)1 therapy. Here, we report that tumor-infiltrating dendritic cell (DC)-specific expression of the deoxyribonuclease, DNASE1L3, is positively correlated with favorable outcomes of anti-PD-(L)1 treatment in cancer patients. DNASE1L3 conditional knockout in DCs leads to enhanced tumor growth and diminishes anti-PD-L1 therapeutic efficacy by impairing infiltration and effector functions of CD8+ T cells. Conversely, injection with DNASE1L3 promotes CD8+ T cell infiltration and reduces exhaustion in the TME, significantly retarding tumor growth and enhancing anti-PD-L1 response. DNASE1L3+ DCs can degrade neutrophil extracellular traps that suppress the spatial distribution of CD8+ T cells in tumors, enabling establishment of cytotoxic CD8+ T cell hubs in human cancers. Our findings reveal a role of DC in regulating intratumoral CD8+ T cells and identify DNASE1L3 as a promising target to improve anti-PD-(L)1 therapy.

Keywords:  CD8(+) T cell; DNASE1L3; anti-PD-1/PD-L1 therapy; cellular community; dendritic cell; immune hubs; neutrophil extracellular traps

DOI:  https://doi.org/10.1016/j.ccell.2025.07.014
Proc Natl Acad Sci U S A. 2025 Aug 19. 122(33): e2501037122

Therapeutic CD8+ T cell tissue retention and immunomodulation during ART interruption fail to prevent SIV rebound.

M Betina Pampena, Sadia Samer, Elise G Viox, Kevin Nguyen, Claire Deleage, Leticia Kuri-Cervantes, James Regan, Vincent H Wu, Steffen Docken, Jeffrey T Safrit, Katharine J Bar, Brandon F Keele, Miles P Davenport, Mirko Paiardini, Michael R Betts.

  A primary obstacle for HIV elimination is the long-term viral reservoir in lymphoid tissues (LT) that can cause rebound viremia if therapy is stopped. Cytotoxic CD8+ T cells are critical for control of HIV and Simian immunodeficiency virus (SIV) viremia; however, CD8+ T cells that migrate to LT are primarily noncytotoxic, calling into question whether these cells could reduce the viral reservoir on antiretroviral therapy (ART) or control viral replication when therapy is halted. To determine whether CD8+ T cells can inhibit viral replication when retained in LT, we inhibited lymphocyte egress from LTs in ART-treated SIV-infected rhesus macaques (RMs) during analytic treatment interruption (ATI) using the S1PR modulator FTY720 alone or in combination with anti-PD1 antibody (αPD1) and the IL-15 receptor superagonist N-803 to increase cytolytic function. FTY720 retained migrating CD4+ and CD8+ T cells in LT, whereas cytotoxic CD8+ T cells remained in the vasculature. After ATI and viral rebound, activated SIV-specific CD8+ T cells increased in frequency in LT of FTY720-treated RMs but failed to become cytotoxic or control plasma viremia compared to controls, even when combined with αPD1 and N-803. These findings indicate that LT-localized CD8+ T cells alone may be insufficient to delay or prevent plasma viral rebound during ATI.

Keywords:  ART; CD8+ T cells; SIV; immunomodulation; lymph nodes

DOI:  https://doi.org/10.1073/pnas.2501037122
Nat Aging. 2025 Aug;5(8): 1377

The immune system offers a window into aging.

DOI: https://doi.org/10.1038/s43587-025-00948-5
Nat Cell Biol. 2025 Aug;27(8): 1208-1209

The liver metabolizes dietary galactose to fuel antitumour T cell immunity.

DOI: https://doi.org/10.1038/s41556-025-01717-7
Nature. 2025 Aug 13.

Expanding the cytokine receptor alphabet reprograms T cells into diverse states.

Yang Zhao, Masato Ogishi, Aastha Pal, Leon L Su, Pingdong Tao, Hua Jiang, Grayson E Rodriguez, Xiaojing Chen, Qinli Sun, Lea Wenting Rysavy, Sam Limsuwannarot, Deepa Waghray, Anusha Kalbasi, K Christopher Garcia.

T cells respond to cytokines through receptor dimers that have been selected over the course of evolution to activate canonical JAK-STAT signalling and gene expression programs1. However, the potential combinatorial diversity of JAK-STAT receptor pairings can be expanded by exploring the untapped biology of alternative non-natural pairings. Here we exploited the common γ chain (γc) receptor as a shared signalling hub on T cells and enforced the expression of both natural and non-natural heterodimeric JAK-STAT receptor pairings using an orthogonal cytokine receptor platform2-4 to expand the γc signalling code. We tested receptors from γc cytokines as well as interferon, IL-10 and homodimeric receptor families that do not normally pair with γc or are not naturally expressed on T cells. These receptors simulated their natural counterparts but also induced contextually unique transcriptional programs. This led to distinct T cell fates in tumours, including myeloid-like T cells with phagocytic capacity driven by orthogonal GSCFR (oGCSFR), and type 2 cytotoxic T (TC2) and helper T (TH2) cell differentiation driven by orthogonal IL-4R (o4R). T cells with orthogonal IL-22R (o22R) and oGCSFR, neither of which are natively expressed on T cells, exhibited stem-like and exhaustion-resistant transcriptional and chromatin landscapes, enhancing anti-tumour properties. Non-native receptor pairings and their resultant JAK-STAT signals open a path to diversifying T cell states beyond those induced by natural cytokines.

DOI: https://doi.org/10.1038/s41586-025-09393-1
Cell Mol Gastroenterol Hepatol. 2025 Aug 11. pii: S2352-345X(25)00153-5. [Epub ahead of print] 101612

Targeting ferroptosis restores the antiviral activity of CD8+ T cells during chronic HBV infection.

Haohao Li, Su Xiao, Chenxin Huo, Shasha Yang, Jun Wang, Xinxing Lan, Menghua Li, Lizhi Shi, Li Zhuo, Jian Zhang, Huajun Zhao, Qiuju Han.

   BACKGROUND & AIMS: CD8+ T cells play a crucial role in antiviral immunity; however, hepatitis B virus (HBV)-specific CD8+ T cells become dysfunctional during chronic HBV (CHB) infection. Blocking inhibitory pathways only partially restores efficient antiviral responses, suggesting that the mechanism underlying CD8+ T-cell dysfunction is complicated. This study aimed to investigate whether HBV-specific CD8+ T cells undergo ferroptosis, examine its correlation with T-cell dysfunction, and elucidate the underlying mechanism and potential intervention strategies.
METHODS: Analysis of CD8+ T cells from CHB patients revealed ferroptosis markers via flow cytometry, electron microscopy, and scRNA-seq, and HBV-specific CD8+ T cells were identified using HBV-core antigen peptide-loaded MHC I tetramer. Flow cytometry, scRNA-seq and additional experimental approaches were employed to investigate the ferroptosis-associated mechanisms in CD8+ T-cell dysfunction.
RESULTS: Ferroptosis was observed in CD8+ T cells from CHB patients, as indicated with increased lipid peroxidation, Fe2+ accumulation and mitochondrial atrophy, particular in HBV-specific CD8+ T cells. Downregulation of GPX4 and upregulation of CD36 were found in CD8+ T cells with high level of lipid peroxidation. Furthermore, ferroptosis is accompanied by impaired antiviral ability. Mechanistically, palmitic acid (PA) upregulates CD36 expression, leading to lipid accumulation; while elevated serum TGF-β1 in CHB patients reduces GPX4 expression and impairs antioxidant capacity. These factors synergistically promote ferroptosis and dysfunction of CD8+ T cells. Treatment with selenium and liproxstain-1 enhanced cytotoxic cytokines production by CD8+ T cells, and subsequently improved antiviral efficacy in vivo.
CONCLUSIONS: Our study demonstrates that ferroptosis drives CD8+ T-cell dysfunction in chronic HBV infection. Targeting ferroptosis pathways may offer a novel therapeutic strategy to restore antiviral immunity.

Keywords:  CD8(+) T-cell dysfunction; Ferroptosis; HBV; Lipid peroxidation

DOI:  https://doi.org/10.1016/j.jcmgh.2025.101612
Curr Opin Clin Nutr Metab Care. 2025 Aug 12.

Recent advances in exercise immunometabolism: Immune cell bioenergetics, muscle-immune cell interactions, and potential dietary adjuvants.

Hashim Islam.

   PURPOSE OF REVIEW: Exercise profoundly alters immunological processes to improve overall health and immunity. The link between immune cell metabolism and function has prompted study of immune cell bioenergetics following acute exercise and the role of muscle-resident immune cells in training adaptations. This review highlights recent work in the area and discusses potential dietary approaches for boosting exercise-induced immunometabolic benefits.
RECENT FINDINGS: Human studies highlight the ability of exercise to alter immune cell bioenergetics, with some also reporting accompanying changes in immune cell function. Rodent studies involving moderate exercise report improved innate and adaptive immune cell phenotypes that are accompanied by increased mitochondrial size and bioenergetic function. Various muscle resident immune cell subpopulations including macrophages, mast cells, and regulatory T cells also appear to be involved in the adaptive responses to exercise. Fasting, exogenous ketones, and mitochondrial enhancing compounds (e.g., sulforaphane, urolithin A) could theoretically potentiate the immunometabolic benefits of exercise based on their independent effects, but evidence for combined interventions is currently lacking.
SUMMARY: Exercise and dietary manipulations that independently alter immunometabolic pathways could be combined to maximize associated health benefits. This may benefit those who cannot meet physical activity guidelines or want to maximize exercise adaptation.

Keywords:  fasting; immunology; inflammation; ketones; mitochondria

DOI:  https://doi.org/10.1097/MCO.0000000000001157
bioRxiv. 2025 Jul 14. pii: 2025.07.09.663913. [Epub ahead of print]

SIRPγ modulates effector differentiation of human CD8 T Cells under suboptimal TCR stimulation: implications for immune homeostasis and autoimmunity.

Megan Morse, Xanthie Rodriguez, Erika DeLaRosa, Sierra Rodriguez, Juma Shanil, Sushmita Sinha.

Background: Aberrant CD8 T-cell differentiation contributes to the pathogenesis of autoimmune diseases, and immune-mediated tissue damage. However, the molecular mechanisms that prevent premature effector T cell programming in humans remain incompletely defined. Signal regulatory protein gamma (SIRPγ) is selectively expressed on T-cells in the human immune system. Notably, genetic variants associated with reduced SIRPγ expression have been linked to increased risk of immune-mediated diseases, including type 1 diabetes and multiple sclerosis, but the contribution of SIRPγ to CD8 T-cell dysregulation in these contexts remains unclear.
Objective: To determine how inter-individual variation in SIRPγ expression influences immune homeostasis and CD8 T-cell effector programming.
Methods: Peripheral blood CD8 T-cells from healthy donors were analyzed for SIRPγ expression and associated differentiation phenotypes. Naïve CD8 T-cells were purified and subjected to siRNA-mediated knockdown of SIRPG , followed by suboptimal TCR stimulation. Differentiation status, transcription factor expression, and effector cytokine production were measured using flow cytometry. CD47 blockade was used to assess ligand dependency.
Results: Low SIRPγ expression on CD8 T-cells was associated with increased frequencies of CD27⁻CD45RO⁺ effector-like and CD27⁻CD45RO⁻ terminally differentiated CD8 T-cells. SIRPG knockdown induced effector-like differentiation, with increased CD45RO and T-bet expression and elevated TNF-α, IFN-γ, and Granzyme B production. This effect was not recapitulated by CD47 blockade, suggesting a CD47-independent regulatory mechanism.
Conclusion: SIRPγ serves as a negative regulator of CD8 T-cell effector differentiation under suboptimal stimulation. Inter-individual variation in its expression may influence susceptibility to immune dysregulation, positioning it as a potential biomarker and therapeutic target.

DOI: https://doi.org/10.1101/2025.07.09.663913
Nat Metab. 2025 Aug 14.

Species-specific serine metabolism differentially controls natural killer cell functions.

Joey H Li, Qinyan Feng, Andréa B Ball, Cassidy D Lee, Michelle L Wallerius, Jan G Bormin, Edmund D Kapelczak, Wesley R Armstrong, Leen Hermans, Abigail Krall, Nedas Matulionis, Tara TeSlaa, Heather R Christofk, Ajit S Divakaruni, Timothy E O'Sullivan.

Immune cells undergo rapid metabolic reprogramming to fuel effector responses. However, whether the metabolic pathways that supply these functions differ between human and mouse immune cells is poorly understood. Using a comparative metabolomics approach, here we show both conserved and species-distinct metabolite alterations in cytokine-activated primary human and mouse natural killer (NK) cells. Activated human NK cells fail to perform de novo serine synthesis, resulting in broadly impaired effector functions when serine starved ex vivo or during in vivo dietary serine restriction, limiting their antitumour function. In contrast, activated mouse NK cells perform de novo serine synthesis to fuel one-carbon metabolism and proliferation, resulting in increased metabolic flexibility during ex vivo and dietary serine restriction. While NK cells from both species require one-carbon metabolism to proliferate and produce interferon-γ, GCLC-dependent glutathione synthesis tunes cytotoxic versus inflammatory function in human NK cells. Thus, activated NK cell functions display species-specific requirements for serine metabolism, and environmental serine availability dictates activated human NK cell functions.

DOI: https://doi.org/10.1038/s42255-025-01348-0
Int J Mol Sci. 2025 Jul 28. pii: 7272. [Epub ahead of print]26(15):

CD1d-Restricted NKT Cells Promote Central Memory CD8+ T Cell Formation via an IL-15-pSTAT5-Eomes Axis in a Pathogen-Exposed Environment.

Yingyu Qin, Yilin Qian, Jingli Zhang, Shengqiu Liu.

  The generation of memory CD8+ T cells is essential for establishing protective T cell immunity against pathogens and cancers. However, the cellular and molecular mechanisms underlying memory CD8+ T cell formation remain incompletely understood. Reliance on specific pathogen-free (SPF) models, characterized by restricted microbial exposure, may limit our understanding of physiologically relevant immune memory development. This study reveals that CD1d-restricted NKT cells regulate central memory T cell (TCM) generation exclusively in a microbe-rich ("dirty") environment. Under non-SPF housing, CD1d+/- and Ja18+/- mice exhibited enhanced TCM formation compared to NKT-deficient controls (CD1d-/-/Ja18-/-), demonstrating that microbial experience is required for NKT-mediated TCM regulation. Mechanistically, CD1d-restricted NKT cells increased IL-15Rα expression on CD4+ T cells in CD1d+/- mice, potentiating IL-15 trans-presentation and thereby activating the IL-15/pSTAT5/Eomes axis critical for TCM maintenance. Functional validation through adoptive transfer of CFSE-labeled OT-1 memory cells revealed an NKT cell-dependent survival advantage in CD1d+/- hosts. This provides direct evidence that microbiota-experienced niches shape immune memory. Collectively, these findings establish CD1d-restricted NKT cells as physiological regulators of TCM generation and suggest their potential utility as vaccine adjuvants to enhance protective immunity.

Keywords:  CD1d-restricted NKT; Eomes; IL-15; central memory CD8+ T

DOI:  https://doi.org/10.3390/ijms26157272
EMBO Rep. 2025 Aug 12.

Hyperactive PLCG1 induces cell-autonomous and bystander T cell activation and drug resistance.

Longhui Zeng, Xinyan Zhang, Yiwei Xiong, Kazuki Sato, Nicole Hajicek, Yasunori Kogure, Keisuke Kataoka, Seishi Ogawa, John Sondek, Xiaolei Su.

  Phospholipase C gamma 1 (PLCG1) has been identified as the most frequently mutated gene in adult T-cell leukemia/lymphoma, suggesting a critical function of PLCG1 in driving T cell activation. However, it remains unclear how these mutations regulate T cell physiology and pathology. Here, we investigate three common leukemia/lymphoma-associated mutations (R48W, S345F, and D1165H). We discover that these mutations induce hyperactive T cell signaling and cause pro-survival phenotypes. PLCG1 mutants enhance LAT condensation, calcium influx, and ERK activation. They also promote T cell proliferation, upregulate cell adhesion molecules, induce cell aggregation, and confer resistance to Vorinostat, an FDA-approved drug for cutaneous T-cell lymphoma. The resistance depends on ERK signaling and can be reversed with an ERK inhibitor. Interestingly, PLCG1 mutants also induce bystander drug resistance in nearby cells expressing wild-type PLCG1. Mechanistically, alpha smooth muscle actin, which is specifically induced by PLCG1 mutants, directly binds PLCG1 to promote its activation. These results demonstrate that hyperactive PLCG1 promotes T cell survival and drug resistance by inducing non-canonical signaling.

Keywords:  Actin; Condensation; ERK; PLCG1; T Cell

DOI:  https://doi.org/10.1038/s44319-025-00546-x
EMBO Mol Med. 2025 Aug 13.

Lymphopenia drives T cell exhaustion in immunodeficient STING gain-of-function mice.

Damien Freytag, Stéphane Giorgiutti, Grégoire Hopsomer, Nadège Wadier, Sabine Depauw, Philippe Mertz, Fabrice Augé, Raphaël Carapito, Isabelle Couillin, Anne-Sophie Korganow, Francesca Pala, Marita Bosticardo, Luigi D Notarangelo, Frédéric Rieux-Laucat, Nicolas Riteau, Peggy Kirstetter, Pauline Soulas-Sprauel.

  STING gain-of-function (GOF) mutations cause STING-Associated Vasculopathy with onset in Infancy (SAVI), a severe autoinflammatory disease. Mice carrying STING GOF V154M mutation develop profound T cell lymphopenia, partly due to impaired thymic development. To investigate the mechanisms of peripheral T cell dysfunctions, we analyzed transcriptomic and phenotypic profiles of splenic T cells from these mice. We found a terminally exhausted T cell phenotype, established early in life upon entry into the periphery, independent of type I interferons and intrinsic STING activation in T cells or stromal cells. Mechanistically, naive T cells in the lymphopenic periphery experienced heightened stimulation of the IL-7 receptor and TCR, including NFAT pathway, a key factor in T cell exhaustion. Transplantation of STING GOF hematopoietic stem cells with wild-type bone marrow prevented exhaustion in this non-lymphopenic context, placing lymphopenia as a key driver. T cell exhaustion was also observed in lymphopenic mice carrying Rag1 hypomorphic mutations. In conclusion, our results highlight T cell exhaustion induced by lymphopenia and could have important implications for the management of patients with severe immune deficiencies.

Keywords:  Homeostasis; Lymphopenia; STING; T Cell Exhaustion

DOI:  https://doi.org/10.1038/s44321-025-00292-6
bioRxiv. 2025 Jul 15. pii: 2025.07.10.664200. [Epub ahead of print]

Pik3ip1/TrIP Regulation of PI3K Restricts CD8 T Cell Anti-Tumor Immunity.

Benjamin M Murter, Lawrence P Kane.

Background: The protein PI3K-interacting protein (PIK3IP1), or transmembrane inhibitor of PI3K (TrIP), is highly expressed by T cells and can modulate PI3K activity in these cells. Several studies have also revealed that TrIP is rapidly downregulated following T cell activation and can play important roles in T cell differentiation.
Methods: We generated mice with CD8-specific TrIP deficiency. We then implanted these mice, and Cre-only control animals, with B16 melanoma or MC38 colon carcinoma tumors. Tumor growth and anti-tumor immunity were then followed. We also assessed the effects of TrIP deficiency on transcriptional programs in CD8 T cells stimulated in vivo or derived from tumor- bearing mice.
Results: We found that activated TrIP KO CD8 T cells display an increased inflammatory transcriptional profile in the absence of TrIP. Consistent with these effects, we also found that knockout of TrIP specifically in CD8 T cells resulted in reduced growth of syngeneic tumors. When characterizing the tumor-infiltrating cells, TrIP KO led to an increase in the number of tumor-infiltrating T cells, as well as a delay in the acquisition of an exhausted phenotype, based on phenotypic and transcriptomic analyses. Finally, our data suggest that TrIP regulates the diversity of T cell clonal responses to tumors, since we observed an increase in the number of distinct T cell clonotypes responding to a tumor neoantigen.
Conclusions: Taken together, our findings demonstrate that TrIP intrinsically restricts the CD8 T cell response to tumors, and that targeting TrIP may augment the anti-tumor response in a way that is distinct from established checkpoint therapies.

DOI: https://doi.org/10.1101/2025.07.10.664200
Mol Ther. 2025 Aug 12. pii: S1525-0016(25)00650-1. [Epub ahead of print]

Asparaginase Enhances CAR-T Cell Antitumor Immunity by Asparagine Metabolic Reprogramming and Induction of Central Memory Phenotype in ALL.

Xinting Zhu, Leng Han, Dingyuan Bai, Lei Yi, Yonghong Zhao, Shuaibing Liu, Run Gan, Bo Xin, Yixing Tu, Jianping Zhang, Yonglong Han, Juan Hao, Zixue Xuan, Cheng Guo, Quanjun Yang.

High levels of asparagine synthetase (ASNS) in acute lymphoblastic leukemia (ALL) lead to immunotherapy resistance. Our study showed ASNS overexpression (OE) in NALM6-GL cancer cells attenuated CAR-T cells mediated cancer cell lysis. Asparaginase (ASPG) is an approved drug that breaks down circulating asparagine in leukemia cells, thereby depriving cancer cells of asparagine and inhibiting cancer growth. We proposed a hypothesis that ASPG engineered CAR-T cells undergo phenotype switching to overcome immunotherapy resistance in ALL. Coculture killing assay showed ASPG-OE CAR-T cells exhibited increased killing efficacy against ASNS - OE cancer cells by enhancing expression of granzyme B, IFN-γ, and TNF-α, whereas ASPG-KO CAR-T cells showed decreased cancer cells lysis efficiency. Phenotypic analysis revealed that ASPG-OE CAR-T cells exhibited distinct phenotypes, including increasing central memory T cells percentage, while decreasing effector memory T cells and effector memory cells that re-expressed CD45RA cells proportions. This distinct phenotype switch of ASPG - OE CAR-T cells toward central memory T cells exerted the increased killing efficacy against NALM6-GL cells even without ASNS-OE. The in vivo xenograft mouse model confirmed that ASPG-OE CAR-T cells exhibited superior anticancer activity against NALM6-GL cancer cells, while ASPG-KO CAR-T cells exhibited inferior anticancer activity. Taken together, ASPG orchestrates CAR-T cell distinct phenotype toward central memory T cells and reprogramming of asparagine metabolism for the enhancing antitumor immunity.

DOI: https://doi.org/10.1016/j.ymthe.2025.08.019
Clin Transl Med. 2025 Aug;15(8): e70441

CD31 regulates metabolic switch in Treg migration attenuates rheumatoid arthritis.

Meijun Liu, Wengqiong Huang, Xiaoli Chen, Zongzhen Meng, Jiawen Yang, Loiola Rodrigo Azevedo, Xiaojiao Zheng, Hao Shen, Wei Jia, Aiping Lyu, Kenneth Cp Cheung.

  CD31 (PECAM-1) plays a critical role in T cell migration, whilst its immunoreceptor tyrosine inhibitory motifs (ITIMs), Y663 and Y686, are recognised for their roles in endothelial function, the precise mechanism in regulating immune cell remains elusive. Here, we demonstrate that CD31 is essential for Treg migration. Upon ITIM engagement, CD31 activates and interacts with the protein tyrosine phosphatase SHP2. In vivo, CD31 Y663F gene transfer recapitulates the wild-type migration phenotype, driven by a metabolic switch to fructose utilisation under the regulation of the PFKFB3 gene. Conversely, the Y686F mutation impairs Tregs migration by disrupting both glycolysis and the switch to fructose metabolism, thus promoting the mitochondrial function via activation of the RNF111/OGT pathway. Our findings reveal a novel role for CD31 ITIMs in orchestrating a metabolic that is switch crucial for Treg migration. This understanding of CD31 polymorphisms and their impact on Treg migration offers potential therapeutic avenues for autoimmune diseases, particularly rheumatoid arthritis (RA). KEY POINTS: CD31 Y663F-mutant Tregs exhibit a glucose-to-fructose metabolic shift, characterised by reduced glucose uptake and enhanced fructose utilisation regulated by PFKFB3. CD31 Y686F mutation disrupts both glycolysis and fructose metabolism in Tregs, shifting energy production towards mitochondrial function via the RNF111/OGT pathway. These findings highlight a novel mechanism by which CD31 ITIMs control Treg migration, offering new therapeutic targets for autoimmune diseases such as RA.

Keywords:  CD31 ITIMs; PFKFB3; RNF111/OGT pathway; Tregs migration; metabolic switch

DOI:  https://doi.org/10.1002/ctm2.70441
Nat Aging. 2025 Aug;5(8): 1455-1470

Understanding and improving vaccine efficacy in older adults.

Sebastian J Hofer, Simon Rapp, Paul Klenerman, Anna Katharina Simon.

Cellular aging of the immune system, commonly referred to as 'immunosenescence', drives a substantial decline in vaccine efficacy among older adults, who are already typically at a higher risk of reduced infection control. Therefore, preventive medicine requires novel strategies to improve vaccination in older adults, particularly by finding ways to mitigate immunosenescence and chronic inflammation. Here, we review how technical innovations, such as increased antigen amounts, improved adjuvants and mRNA-based and universal vaccines, can complement traditional methods of improving vaccination success in older adults. Furthermore, we discuss emerging clinical evidence suggesting that geroscience interventions, such as mTOR inhibition and caloric restriction, can enhance vaccine outcomes in older adults, potentially by targeting molecular aspects of immunosenescence and systemic characteristics of aging, including metabolic changes in the blood and chronic inflammation. Ultimately, we propose that integrating geroscience with tailored immunization could attenuate the effects of immune aging on vaccination efficacy in older populations.

DOI: https://doi.org/10.1038/s43587-025-00939-6