bims-imseme 2026-02-08 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–02–08
thirty-two papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

Zbtb32 promotes CD8+ T cell differentiation and function in cancer.
Antigen-specific TH17 cells offset the age-related decline in durable T cell immunity.
Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch.
T-cell exhaustion from a multiomics perspective: Differentiation mechanisms and regulatory networks in the journey from progenitor-Exhausted T cells to terminally exhausted T cells.
Multi-Omics Analysis of Human Blood Cells Reveals Unique Features of Age-Associated Type 2 CD8 Memory T Cells.
Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.
Macrophage-derived chemokines in T cell regulation: implications for cancer immunotherapy.
Synthetic Hybrid Receptors for Safer and Programmable T Cell Therapy.
T Cell Exhaustion in Hepatocellular Carcinoma: A Substantial Barrier in Immunotherapy.
NR4A1 limits CD8⁺ T Cell effector responses and protection in tuberculosis.
NR4A1 limits CD8 + T Cell effector responses and protection in tuberculosis.
Metabolic reprogramming tailors T cell immunity in sepsis.
Targeting epigenetic regulators to boost T cell immunotherapy against cancer.
Mechanisms of FOXK1-regulated glycolipid metabolism in mediating TOX-induced histone lactylation to promote CD8⁺ T cell exhaustion in high-grade serous ovarian cancer.
TCF1 lo CD8 T cells proliferate and persist autonomously in tumors.
Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in Chronic HIV-1 Infection.
Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.
A multipronged Tα1 reset of CD8+ T cell cytotoxicity against breast cancer.
Single-cell immune atlas of mouse testes unveils metabolic reprogramming of FOLR2 + macrophages in orchestrating testicular immunity during aging.
Stepwise differentiation from precursor intermediates and distinct Th1 checkpoints promote CD4 Th1 cell differentiation during chronic viral infection.
Ibrutinib enhances stem-cell-memory T cell generation during early T cell activation but inhibits T cell proliferation.
Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.
Mechanistic insights into stem cell aging: Pathways and processes.
Macrophage immunosenescence prolongs intraocular inflammation in aged mice via impaired induction of regulatory T cells.
Ageing and liver immune cells.
Clonal expansion of cytotoxic CD8⁺ T cells in lecanemab-associated ARIA.
Atlas-guided discovery of transcription factors for T cell programming.
CD4+ to CD8+ T cell imbalance drives poor Achilles tendon repair in patients.
Mouse and human T cell Cas9-RNP/nucleofection-mediated gene-editing.
Tumour-intrinsic features shape T cell differentiation through precursor to symptomatic multiple myeloma.
Fatty acid uptake mediated by FABP4 promotes the formation of CD8+T cell senescence through lipid peroxidation in the adipocyte-rich microenvironment of Ovarian Cancer.
Polysialylated CD56 drives immune evasion in clear cell renal cell carcinoma via engagement of the Siglec-7 checkpoint on CD8+ T cells.

J Exp Med. 2026 Apr 06. pii: e20250005. [Epub ahead of print]223(4):

Zbtb32 promotes CD8+ T cell differentiation and function in cancer.

Birui Pan, Qinli Sun, Ruifeng Li, Juan Feng, Jing Hao, Bowen Xie, Xiaohong Zhao, Zixuan Zhao, Peng Wei, Qiuyan Lan, Shiyuan Xie, Tian Xie, Yongzhen Chen, Kun Wei, Xuan Zhong, Hai Qi, Ling Ni, Chen Dong.

In the tumor microenvironment (TME), "exhausted" CD8+ T cells are classified into progenitor (Tpex) and terminally exhausted (Ttex) populations. Tpex cells, critically regulated by zinc finger and BTB domain containing 27 (Zbtb27)/Bcl6 transcription factor, could be reinvigorated during immune checkpoint blockade (ICB) therapy, while Ttex cells, characterized by stronger proliferation and cytotoxicity, play an indispensable role in tumor control. However, the mechanisms governing the differentiation into Ttex and their function remain not well understood. In this study, we identified that Zbtb32, highly expressed in CD8+ Ttex subset, is crucial for CD8+ T cells within tumors. Zbtb32, regulated by CD28 signaling, promotes the differentiation of CD8+ T cells into Ttex subset, enhancing their cytotoxicity, proliferation, and anti-tumor capability. Importantly, we found a competitive DNA binding between Zbtb32 and Bcl6, especially in regulation of Id2 expression. Thus, our findings demonstrate the pivotal role of Zbtb32 in CD8+ T cell anti-tumor function, with implications in cancer immunotherapy.

DOI: https://doi.org/10.1084/jem.20250005
Sci Adv. 2026 Feb 06. 12(6): eaea7131

Antigen-specific TH17 cells offset the age-related decline in durable T cell immunity.

Ines Sturmlechner, Abhinav Jain, Jingjing Jiang, Hirohisa Okuyama, Yunmei Mu, Maryam Own, Cornelia M Weyand, Jörg J Goronzy.

Older adults are susceptible to infections in part due to waning of immune memory. To uncover mechanisms of a long-lasting immune memory, we contrasted varicella zoster virus antigen-specific memory T cell responses in adults vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine conferring durable protection only when given at young age or with an adjuvanted component vaccine eliciting long-lasting immunity in older adults. Unlike VZV-specific CD4+ T cells, CD8+ T cells exhibited profound age-sensitive changes including memory subset shifts, reduced T cell receptor diversity, and loss of stem-like features. Vaccination of older adults with the adjuvanted vaccine did not restore CD8+ defects but selectively enhanced T helper 17 (TH17) CD4+ T cells and prevented their conversion into regulatory T cells, likely through lipid metabolic regulation. Thus, durable vaccine efficacy with aging relies on antigen-specific TH17 cells that compensate for CD8+ T cell defects.

DOI: https://doi.org/10.1126/sciadv.aea7131
bioRxiv. 2026 Jan 17. pii: 2026.01.16.699963. [Epub ahead of print]

Glucose availability tunes latent CD8+ T cell expansion potential through a mitogen-independent, mTOR-dependent regulatory switch.

Tran Ngoc Van Le, Krittin Trihemasava, Lucien Turner, Kelly Rome, Aaron Wu, Will Bailis.

Mitogenic signals are understood to license cell cycle progression and the metabolic reprogramming required for cell division, with acquired nutrients serving as permissive substrates. Here, we show that nutrient availability instead functions as a mitogen-independent regulatory input that dynamically controls CD8+ T cell proliferative potential. Activating stimuli have been shown to set T cell expansion capacity through their control of c-Myc expression, with the rate of c-Myc decay functioning as a division timer. We demonstrate that nutrient availability is sufficient to control c-Myc expression dynamics and dictates how division potential is stored and later actualized. Glucose-restricted T cells sustain proliferative potential and exhibit high AKT and ERK phosphorylation, despite limited growth. Upon glucose restoration, these cells rapidly increase c-Myc expression, accelerate through the cell cycle, and return to the expansion potential of glucose-replete controls, even after days of enforced restriction. Glucose restriction thus maintains a latent metabolic and mitogenic signaling state that is rapidly realized upon recovery. Mechanistically, mTOR signaling is required for this glucose recovery-driven proliferation, despite c-Myc and pERK remaining elevated following mTOR inhibition, indicating that glucose and mitogen signals operate through parallel rather than hierarchical control points. Altogether, these findings reveal that nutrient availability is not merely rate-limiting for proliferation but dictates the kinetics at which mitogenic signals are dissipated and realized. While mitogenic and nutrient cues converge on a shared anabolic network, they operate through distinct regulatory arms to coordinate the tempo and magnitude of clonal expansion, with implications for protective immunity and immunotherapy.
Significance Statement: CD8+ T cells rapidly proliferate to fight infections and cancer, often in variable nutrient environments. Activation signals are understood to control T cell expansion potential by setting c-Myc expression and its subsequent decay, with nutrients providing fuel. Here we find that glucose availability functions as an independent regulatory switch. Glucose-restricted T cells remain proliferatively poised for days, keeping pro-growth signaling and metabolic capacity primed. Upon glucose restoration, cells undergo a proliferative burst and catch up to glucose-replete counterparts. Although c-Myc expression rises upon glucose restoration, accelerated division kinetics instead require mTOR activity. These findings reveal that nutrient availability operates in parallel with mitogenic signaling, tuning the rate at which T cells store and realize their expansion potential.

DOI: https://doi.org/10.64898/2026.01.16.699963
Clin Transl Med. 2026 Feb;16(2): e70609

T-cell exhaustion from a multiomics perspective: Differentiation mechanisms and regulatory networks in the journey from progenitor-Exhausted T cells to terminally exhausted T cells.

Tong Zhu, Xiaoyu Teng, Qinlian Jiao, Yidan Ren, Yunshan Wang, Maoxiao Feng.

  A central hurdle limiting the success of T-cell-based immunotherapies is the progressive dysfunction of T cells, known as exhaustion. Overcoming this exhausted state is therefore a pivotal objective in translational oncology and immunology. The advent of single-cell multiomics has fundamentally revised the once-prevailing view of exhaustion as a uniform endpoint. Instead, it is now recognised as a dynamic differentiation process comprising a spectrum of distinct cellular states. This spectrum is organised along a hierarchical axis, originating from progenitor-exhausted (Tpex) cells that retain proliferative potential and advancing towards terminally exhausted (Tex) populations with severely impaired effector functions. We undertake a comprehensive synthesis of multiomics data-spanning transcriptomic, epigenomic, metabolomic, proteomic and posttranslational modification (PTM)-proteomic layers-to decipher the interconnected regulatory programmes that dictate commitment along this exhaustion axis. From this integrated analysis, we derive a unified mechanistic framework that delineates the molecular drivers of Tpex cell fate determination and terminal exhaustion. Beyond its explanatory power for basic biology, this framework serves as a direct roadmap for therapeutic innovation, highlighting novel nodes for intervention aimed at reinvigorating the exhausted T-cell compartment. The practical application of these insights holds significant promise for enhancing the efficacy of established current immunotherapeutic platforms. KEY POINTS: This review is the first to integrate multi-omics evidence for constructing a dynamic regulatory map of T-cell exhaustion. It highlights the critical cross-omics synergistic mechanisms, such as metabolic reprogramming influencing epigenetic remodeling to drive cell fate. The multi-omics perspective presented directly informs novel therapeutic strategies.

Keywords:  PTM proteomics; Tpex; T‐cell exhaustion; cancer immunotherapy; epigenomics; metabolomics; proteomics; single‐cell multiomics; terminally exhausted T cells; transcriptomics

DOI:  https://doi.org/10.1002/ctm2.70609
Aging Cell. 2026 Feb;25(2): e70393

Multi-Omics Analysis of Human Blood Cells Reveals Unique Features of Age-Associated Type 2 CD8 Memory T Cells.

Hiroyuki Matsui, Marlene Cervantes, Mir M Khalid, Alan Tomusiak, Varun Dwaraka, Jorge Landgrave-Gomez, Prasanna Vadhana Ashok Kumaar, Qingwen Chen, Jessica Lasky-Su, Jake Stone, Ritesh Tiwari, Ryan Kwok, Shuntaro Ichikawa, Benjamin D Ambrose, Rebeccah R Riley, Genesis Vega Hormazabal, Ariel Adkisson-Floro, Andreea Cristina Alexandru, Ryan Smith, Birgit Schilling, Herbert G Kasler, Eric Verdin.

Aging impacts immune function, but the mechanisms driving age-related changes in immune cell subsets remain unclear. To explore age-dependent changes in immune cell populations, we analyzed human peripheral blood mononuclear cells (PBMCs) from a cohort of healthy donors aged 20-82 years using a 36-color spectral flow cytometry panel focused on T cells. We identified a unique population of memory CD8 T cells, which lack CXCR3 and produce a Th2-like cytokine response, and accumulate with age. We discovered an age-dependent bias in naïve CD8 T cells toward Th2 cytokine production, accompanied by transcriptional and epigenetic changes supporting this phenotype. Moreover, health outcome association analysis linked the accumulation of these unique CXCR3- central memory CD8 T cells to asthma, chronic liver conditions, and type 2 diabetes. Together, our results support the model that an age-dependent drift in epigenetic regulation toward a Th2-like phenotype drives a pathogenic Th2-like immune population.

DOI: https://doi.org/10.1111/acel.70393
Nat Commun. 2026 Feb 04.

Cytoplasmic NAD/H synthesis via NRK1 regulates inflammatory capacity and promotes survival of CD4+ T cells.

Victoria Stavrou, Myah Ali, Nancy Gudgeon, Emma L Bishop, Taylor Fulton-Ward, Bethany Turley, Silke Heising, Sally H Mohamed, Sofia Hain, Lorna George, Minghao Deng, Jack McCowan, Lozan Sheriff, Scott P Davies, Bryan Marzullo, Daniel A Tennant, Craig L Doig, David A Bending, Ed W Roberts, Gareth G Lavery, Rebecca A Drummond, Sarah Dimeloe.

T cell metabolism increases upon activation, underpinning immune effector functions. Nicotinamide adenine dinucleotide (NAD/H) is an essential redox cofactor for glycolysis and mitochondrial substrate oxidation. It's phosphorylation to NADP/H regulates reactive oxygen species (ROS) abundance. NAD/H levels increase upon T cell activation, but synthesis pathways and implications are not fully characterised. Here, we interrogate the role of the NAD/H-synthesis enzyme nicotinamide riboside kinase 1 (NRK1), the expression of which increases upon stimulation of both human and murine CD4+ T cells. Functionally, NRK1 activity restrains activation and cytokine production of CD4+ T cells while promoting survival. These activities are linked to increased NRK1 expression in the cytoplasm, where it locally raises NAD/H levels. This supports glycolysis, but more profoundly impacts cytoplasmic NADP/H generation, thereby controlling ROS abundance and nuclear NFAT translocation. During fungal and viral infection, T-cell-intrinsic NRK1 maintains effector CD4+ T cell abundance within affected tissues and draining lymph nodes, supporting infection control. Taken together, these data confirm that subcellular regulation of immune cell metabolism determines immune responses at the level of whole organism.

DOI: https://doi.org/10.1038/s41467-026-68863-w
Front Immunol. 2025 ;16 1739154

Macrophage-derived chemokines in T cell regulation: implications for cancer immunotherapy.

Kunpeng Zhang, Jingjing Liu, Qi Liu, Ningning Zhu, Baodong Ye.

  Macrophages are pivotal regulators of immunity, with intercellular communication being a central mechanism of their function. Among these communications, chemokines act as critical messengers in macrophage-T cell crosstalk. This review systematically elucidates the notable roles of macrophage-derived chemokines in modulating T cell homeostasis, particularly concentrating on their influence on both CD4+ and CD8+ T cell differentiation, proliferation, exhaustion, secretory activity, metabolic reprogramming (involving glycolysis and OXPHOS), chemotaxis, and memory formation. In the tumor microenvironment (TME), the dualistic nature of chemokines was highlighted: tumor-associated macrophages (TAMs) could secrete immunosuppressive factors, such as CCL22 and CCL5, recruiting inhibitory cells and inducing CD8+ T cell exhaustion. In contrast, M1-like macrophages could produce CXCL9 and CXCL10, activating effector CD8+ T cells, thereby enhancing anti-tumor immunity. Finally, the promising therapeutic potential of targeting specific chemokine signaling axes, such as CCL2/CCR2 and CXCL10/CXCR3, was discussed as a strategy to improve the efficacy of cancer immunotherapy.

Keywords:  T cells; cancer immunotherapy; chemokines; macrophages; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1739154
bioRxiv. 2026 Jan 23. pii: 2026.01.22.701150. [Epub ahead of print]

Synthetic Hybrid Receptors for Safer and Programmable T Cell Therapy.

Maxwell G Foisey, Julie Garcia, Xun Li, Xiaoyu Yang, Claire Hilburger, Chloe Thienpont, Alejandro Chaves-Martinez, Serkan Belkaya, Tina Truong, Iowis Zhu, Raymond Liu, Axel Hyrenius-Wittsten, Ricardo Almeida, Brian R Shy, Greg M Allen, Sarah Wyman, Kole T Roybal.

Engineered T cell therapies have achieved significant clinical success in hematological malignancies but remain largely ineffective in solid tumors. Overcoming this limitation requires strategies that enhance T cell function while avoiding systemic immune toxicities and pathological T cell states. Existing approaches typically rely on constitutive gene overexpression or suppression to augment potency or remodel the tumor microenvironment, but these strategies frequently lead to dysregulated immune activation and dose-limiting toxicity. Here, we present Hybrid Receptors (Hybrid-Rs), a modular receptor platform that integrates features of chimeric antigen receptors (CARs) and SyNthetic Intramembrane Proteolysis Receptors (SNIPRs) to couple antigen-dependent T cell activation with programmable gene regulation. Hybrid-Rs enable precise, context-dependent control of T cell potency, differentiation states, and conditional expression of secreted immunotherapeutic payloads with otherwise prohibitive toxicity. Hybrid-Rs are readily humanized and compatible with precision genome editing in primary human T cells, providing a direct and practical path to clinical translation.

DOI: https://doi.org/10.64898/2026.01.22.701150
J Cell Mol Med. 2026 Feb;30(3): e71044

T Cell Exhaustion in Hepatocellular Carcinoma: A Substantial Barrier in Immunotherapy.

Kosar Nouri, Negar Asadollahei, Yasamin Haghir-Sharif-Zamini, Homeyra Seydi, Mahsa Salehi, Mehrnaz Mesdaghi, Mustapha Najimi, Massoud Vosough.

  Hepatocellular carcinoma (HCC), accounting for over 90% of primary liver cancers, remains a major global challenge for healthcare professionals. While immunotherapy has transformed the landscape of cancer treatment, its success is often limited by immune resistance, particularly through T cell exhaustion which remains a major barrier to effective immune responses in solid tumours, including HCC. As tumours progress, T cells undergo a gradual loss of functionality due to continuous antigen exposure and fail to exert effective anti-tumour responses. During this process, alterations in the epigenome, transcriptome, signalling pathways, and tumour metabolome, in addition to interactions with other cells in the tumour microenvironment, efficiently contribute to T cell exhaustion. Restoring T cell function brings hope for improving therapy outcomes and providing new treatment modalities for HCC patients. In this review, we explore the key cellular and molecular mechanisms driving T cell exhaustion, including the roles of immunosuppressive cells, metabolic stress, and epigenetic alterations focusing on HCC. We also discuss current and emerging strategies aimed at preventing or reversing T cell exhaustion, such as epigenetic modulation, immune checkpoint blockade, metabolic reprogramming, and combination therapies. Understanding these interconnected pathways is critical for designing more effective immunotherapy-based approaches for liver cancer.

Keywords:  T cell exhaustion; epigenetic modifications; hepatocellular carcinoma; signalling pathways; solid tumour immunotherapy; tumour metabolomics

DOI:  https://doi.org/10.1111/jcmm.71044
Res Sq. 2026 Jan 13. pii: rs.3.rs-8363336. [Epub ahead of print]

NR4A1 limits CD8⁺ T Cell effector responses and protection in tuberculosis.

Amit Singhal, Samreen Fatima, Yao Chen, Lorissa Smulan, Basanthi Satish, Mike Jameson, Sheetal Saini, Calvin Johnson, Alicia Tay, Shihui Foo, Hedayathulla Rahmathulla, Akhila Balachander, Shanshan Howland, Hardy Kornfeld.

During Mycobacterium tuberculosis (Mtb) infection, CD8⁺ T cells exhibit dysfunction with impaired cytotoxicity and limited localization to granuloma cores. Using knockout mice, adoptive-transfer models and validation in macaque and human datasets, we identified the nuclear receptor NR4A1 as a key restrainer of CD8+ T cell immunity in tuberculosis (TB). Mtb-infected Nr4a1-/- mice displayed reduced bacterial burden, attenuated pathology, higher lung CD8⁺/CD4⁺ T cell ratios, and enhanced CD8⁺ T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion of Nkg7+ and Granzyme+ cytotoxic CD8⁺ T cell subsets in Nr4a1-/- mice. Spatial analyses demonstrated increased infiltration of Nkg7+ activated CD8⁺ T cells in Nr4a1-/- lesions. ChIP-qPCR showed NR4A1 binding to Nkg7 promoter, and Nkg7 knockdown abrogated the enhanced cytotoxicity of Nr4a1-/- CD8+ T cells. Pharmacologic inhibition of NR4A1 reduced Mtb burden and pathology, and restored Nkg7 expression and CD8+ T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8⁺ T cell-mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target.

DOI: https://doi.org/10.21203/rs.3.rs-8363336/v1
bioRxiv. 2026 Jan 13. pii: 2026.01.12.699051. [Epub ahead of print]

NR4A1 limits CD8 + T Cell effector responses and protection in tuberculosis.

Samreen Fatima, Yao Chen, Lorissa Smulan, Basanthi Satish, Mike Jameson, Sheetal Saini, Calvin Johnson, Alicia Tay, Shihui Foo, Hedayathulla Rahmathulla, Akhila Balachander, Shanshan W Howland, Hardy Kornfeld, Amit Singhal.

During Mycobacterium tuberculosis ( Mtb ) infection, CD8 + T cells exhibit dysfunction with impaired cytotoxicity and limited localization to granuloma cores. Using knockout mice, adoptive-transfer models and validation in macaque and human datasets, we identified the nuclear receptor NR4A1 as a key restrainer of CD8 + T cell immunity in tuberculosis (TB). Mtb -infected Nr4a1 -/- mice displayed reduced bacterial burden, attenuated pathology, higher lung CD8 + /CD4 + T cell ratios, and enhanced CD8 + T cell effector functions. Bulk and single-cell RNA sequencing revealed suppression of gene expression program linked with exhaustion, and expansion of Nkg7 + and Granzyme + cytotoxic CD8 + T cell subsets in Nr4a1 -/- mice. Spatial analyses demonstrated increased infiltration of Nkg7 + activated CD8 + T cells in Nr4a1 -/- lesions. ChIP-qPCR showed NR4A1 binding to Nkg7 promoter, and Nkg7 knockdown abrogated the enhanced cytotoxicity of Nr4a1 -/- CD8 + T cells. Pharmacologic inhibition of NR4A1 reduced Mtb burden and pathology, and restored Nkg7 expression and CD8 + T cell infiltration in the lung. Together, these findings identify NR4A1 as a negative regulator of CD8 + T cell-mediated immunity in TB and suggest the NR4A1-NKG7 axis as a novel host-directed therapeutic target.
A one-sentence summary of your paper: NR4A1 suppresses CD8 + T cell infiltration and cytotoxicity in TB lesions, and its inhibition enhances host resistance to Mtb infection.

DOI: https://doi.org/10.64898/2026.01.12.699051
Front Immunol. 2025 ;16 1679493

Metabolic reprogramming tailors T cell immunity in sepsis.

Di Xian, Feng Chen, Bing Liu, Lei Wang.

  Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection, characterized by persistently high morbidity and mortality. Current treatment strategies have limitations, particularly the persistence of an immunosuppressed state. Recent studies have revealed that sepsis not only causes immune system dysregulation but also leads to metabolic disturbances, specifically metabolic reprogramming in T cells-a field still in its early stages. This review systematically explores the mechanisms of T-cell metabolic reprogramming in sepsis, including enhanced glycolysis, mitochondrial dysfunction, and dysregulated amino acid metabolism. It further analyzes how these alterations, mediated by signaling pathways such as HIF-1α, mTOR, and AMPK, as well as key metabolic enzymes, exacerbate T-cell exhaustion and immunosuppression. The article elaborates on the role of metabolic reprogramming in T-cell dysfunction and susceptibility to secondary infections, and summarizes potential therapeutic strategies targeting metabolic pathways-such as IL-7 therapy and IDO1 inhibitors-for restoring T-cell function, offering new directions for sepsis immunotherapy.

Keywords:  T-cell immunity; immunosuppression; metabolic reprogramming; sepsis; therapeutic strategies

DOI:  https://doi.org/10.3389/fimmu.2025.1679493
Cell Biosci. 2026 Feb 03.

Targeting epigenetic regulators to boost T cell immunotherapy against cancer.

Tiaojiang Xiao, Ying E Zhang.

  Epigenetic regulation is crucial in directing T-cell differentiation, function, and fate, thereby influencing the success of T-cell-based immunotherapies. This review begins with an overview of the evolution of T-cell immunotherapies in cancer treatment. We then examine key epigenetic regulators-such as DNA methylation, mRNA methylation, and histone methylation-and their roles in shaping T-cell states during infection and tumorigenesis. The contributions of these regulators to T-cell exhaustion and lineage commitment are discussed in the context of immunotherapy efficacy. We highlight recent advances in targeting epigenetic pathways to enhance CAR-T and TCR-based therapies and conclude with current challenges and emerging strategies to improve the durability and effectiveness of adoptive T-cell therapies.

Keywords:  Chromatin modification; Epigenetic regulator; T-cell based immunotherapy; Tumor microenvironment (TME)

DOI:  https://doi.org/10.1186/s13578-026-01533-y
Sci Rep. 2026 Feb 03.

Mechanisms of FOXK1-regulated glycolipid metabolism in mediating TOX-induced histone lactylation to promote CD8⁺ T cell exhaustion in high-grade serous ovarian cancer.

Min Li.



Keywords:  CD8⁺ t cell exhaustion; CD8⁺ t cells; FOXK1; High-grade serous ovarian cancer; Immune checkpoint; TOX

DOI:  https://doi.org/10.1038/s41598-025-32938-3
bioRxiv. 2026 Jan 21. pii: 2026.01.17.700120. [Epub ahead of print]

TCF1 lo CD8 T cells proliferate and persist autonomously in tumors.

Megan M Erwin, Natalie R Favret, Claudia N McDavid, Zachary D Ewell, Melissa M Wolf, Lincoln A Brown, Jessica J Roetman, Michael W Rudloff, Kristen A Murray, Carlos R Detrés Román, Mary Philip.

Cancers develop in humans over months to years, and tumor-specific CD8 T cells (TST) can interact with cancer cells throughout tumorigenesis. Nevertheless, the long-term population dynamics of TST, especially within progressing tumors, are not well understood. A paradigm first established in chronic viral infection and applied to tumors describes a population hierarchy among exhausted T cells. Progenitor/stem-like exhausted T cells, which express the transcription factor T cell factor 1 (TCF1), maintain the population through self-renewal and by giving rise to terminally differentiated TCF1 lo progeny. This has led to a focus on TCF1 hi T cells, and though TCF1 lo CD8 T cells are the predominant tumor-infiltrating/tumor-reactive subtype in patients, they have been largely overlooked. We leveraged our autochthonous liver cancer model to analyze TST differentiation and proliferation throughout tumorigenesis. Dual EdU/BrdU labeling studies revealed that throughout tumorigenesis, a subset of TCF1 lo TST in the liver stochastically entered and exited cell cycle, and at later time points there was no evidence of a TCF1 hi progenitor-like population. Moreover, TCF1-knockout TST proliferated and persisted robustly in tumors. Using liver cancer and melanoma models, we showed that tumor-resident TCF1 lo TST proliferate and persist autonomously, even when new TST influx into tumors is inhibited. The prevailing notion is that only TCF1 hi TST self-renew but we now demonstrate, using a clinically relevant mouse cancer model, that TCF1 lo TST stochastically proliferate to achieve long-term population maintenance. Future studies to understand and harness this mechanism to improve T cell persistence in tumors could lead to novel immunotherapies for patients with cancer.
SYNOPSIS: We show that tumor-specific T cells with little/no expression of TCF1, previously considered incapable of self-renewal, can proliferate stochastically and persist long-term. As TCF1 lo CD8 T cells are often the predominant tumor-reactive T cells found in tumors, future studies should be aimed at reprogramming these proliferating T cells within tumors.

DOI: https://doi.org/10.64898/2026.01.17.700120
bioRxiv. 2026 Jan 14. pii: 2026.01.13.699280. [Epub ahead of print]

Microbiome-Derived Metabolites Shape CD4⁺ T-Cell Differentiation and Immune Aging in Chronic HIV-1 Infection.

Amanda Cabral Da Silva, Luke Flantzer, Jaclyn Weinberg, Shuya Kyu, Lisa Daley-Bauer, Ana Carolina Santana, Aarthi Talla, Amber Lynn Rittgers, Sarah Welbourn, David Ezra Gordon, Jeffery Alan Tomalka, Vincent C Marconi, Dean P Jones, Souheil-Antoine Younes.

The role of aromatic gut-derived bacterial metabolites (GDBMs) in shaping immune cell metabolism and function remains poorly explored. Using ex vivo metabolomic profiling of paired plasma and CD4⁺ T-cells from people living with HIV-1 (PLWH), we identified a network of aromatic GDBMs whose cell-associated abundance, rather than systemic levels, was linked to broad alterations in CD4⁺ T-cell metabolic and functional states. Among these metabolites, p-cresol sulfate (PCS) emerged as a mechanistic prototype investigated in depth. Ex vivo flow cytometry and single-cell RNA sequencing of CD4⁺ T-cells stratified by cell-associated PCS levels revealed dose-dependent enrichment of transcriptional programs associated with impaired differentiation capacity, regulatory-like identity, and cellular senescence. Consistently, in vitro transcriptomic and proteomic analyses of PCS-exposed CD4⁺ T cells demonstrated induction of cell-cycle arrest, mitochondrial dysfunction, and senescence-associated programs, including upregulation of p16 and p21. Integration of these immunometabolic features with measurements of HIV-1 reservoir size in PLWH revealed that CD4⁺ T-cell states defined by cell-associated GDBMs track with intact proviral DNA levels in vivo. Together, these findings define a microbiome-derived axis that reshapes CD4⁺ T-cell metabolism and fate and promotes immune aging-associated states in PLWH. Our data suggest that cell-associated GDBMs may foster immunometabolic CD4⁺ T-cell states previously linked to long-term HIV-1 reservoir persistence in vivo.

DOI: https://doi.org/10.64898/2026.01.13.699280
Sci Immunol. 2026 Feb 06. 11(116): eaef9196

Aldehyde and seek: Toxic aldehydes drive exhaustion in tumor-infiltrating T cells.

Cait A McAlindon, Rachael A Clark.

Aldehydes accumulating in response to reduced fatty acid oxidation in tumor-infiltrating lymphocytes damage mitochondria and drive T cell exhaustion.

DOI: https://doi.org/10.1126/sciimmunol.aef9196
Hum Immunol. 2026 Jan 30. pii: S0198-8859(26)00024-8. [Epub ahead of print]87(3): 111678

A multipronged Tα1 reset of CD8+ T cell cytotoxicity against breast cancer.

Smriti Mishra, Gaurang Telang, Anurag Sureshbabu, Samruddhi Kulkarni, Senthil Thayagrajan, A W Santhosh Kumar, Rajshri Singh.

  Thymosin α1 (Tα1) is an endogenous thymic peptide that enhances immune competence through activation of T cells, dendritic cells, and innate immune pathways. However, its direct impact on CD8+ T cell-mediated antitumor immunity in breast cancer remains unclear. In this study, CD8+ T cells isolated from peripheral blood of ten healthy donors were cultured under unstimulated, CD3/CD28-stimulated, Tα1-treated, or exhaustion-rescue conditions to evaluate cytotoxic activity against MDA-MB-231 breast cancer cells and CD44+ cancer stem-like cells (CD44+ CSC-like cells). Tα1 significantly enhanced CD8+ T cell-mediated apoptosis, suppressed tumor cell proliferation, and increased granzyme B secretion beyond CD3/CD28 stimulation alone. In exhausted T cells, Tα1 partially restored effector function and reduced PD-1, TIM-3, and LAG-3 expression. Complementary transcriptomic analysis using a compact four-gene Tα1 Response Index (Tα1-RI: TLR9, TLR2, IRF1, NLRC5) in TCGA-BRCA (n = 1,112) confirmed positive correlations with antigen presentation and cytotoxic programs and enrichment in CD8-like T cells in single-cell datasets. Collectively, these findings demonstrate that Tα1 enhances CD8+ T cell cytotoxicity while alleviating exhaustion, supporting its potential as an adjunct immunomodulator for improving immune surveillance in breast cancer.

Keywords:  Breast cancer; CD8(+) T cells; CSC-like cells; T cell exhaustion; Thymosin α1

DOI:  https://doi.org/10.1016/j.humimm.2026.111678
Geroscience. 2026 Jan 30.

Single-cell immune atlas of mouse testes unveils metabolic reprogramming of FOLR2 + macrophages in orchestrating testicular immunity during aging.

Xinyu Li, Min Zhang, Ani Chi, Jiahui Mo, Xiaofeng Tan, Hongde Chen, Chunhua Deng, Xiangzhou Sun, Xin Feng, Zhihong Chen.

  Immune cells play a crucial role in maintaining tissue homeostasis during aging. However, the dynamics and functions of immune cells in testicular aging have not been well elucidated. In this study, we utilized single-cell RNA sequencing (scRNA-seq) to analyze CD45-enriched immune cells isolated from young and old mice testis. This approach yielded a comprehensive dataset comprising 6622 immune cells, encompassing macrophages, monocytes, and T cells. Our analysis revealed a significant decline in FOLR2 + resident macrophages, accompanied by a corresponding increase in pro-inflammatory CD74 + macrophages, CCR2 + monocytes, and CD8 + T cells in old mice testis. These findings were further validated by multiplex immunofluorescence staining. Notably, during testicular aging, FOLR2 + macrophages underwent a phenotypic transition towards a pro-inflammatory state. This transition subsequently facilitated the recruitment of monocytes and CD8 + T cells via the CCL8-CCR2/CCR5 axis. Furthermore, we discovered that mitochondrial metabolic dysfunction was a key driver of FOLR2 + macrophage activation. Specifically, inhibition of IDH2, a key catalytic enzyme in the TCA cycle, significantly induced this activation. Collectively, our findings provide a detailed immune atlas of testicular aging and suggest a potential role for FOLR2 + macrophages in maintaining testicular immune homeostasis.

Keywords:  CCL8-CCR2/CCR5 axis; Macrophages; Mitochondrial metabolism; Single-cell RNA sequencing; Testicular aging

DOI:  https://doi.org/10.1007/s11357-026-02109-x
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2522928123

Stepwise differentiation from precursor intermediates and distinct Th1 checkpoints promote CD4 Th1 cell differentiation during chronic viral infection.

Hongshen Niu, Siying Lin, Ryan Brown, Jian Shen, Arjun Kharel, Yuqi Zhang, Kexin Gai, Ashley Bauer, Ashley Brown, Ziyang Xu, David G Brooks, Weiguo Cui.

  CD4+ helper T cells are essential for controlling viral infections. During chronic LCMV infection, CD4+ T cells differentiate into heterogeneous populations, including a TCF-1hi progenitor subset that serves as a reservoir to continuously replenish type 1 helper (Th1) and follicular helper (Tfh) T cells. The gradual loss of CD4+ Th1 cell responses impairs the immune system's ability to control viral replication and contributes to the development of CD8+ T cell exhaustion. However, the mechanisms directing Th1 differentiation and the factors underlying their progressive decline during chronic infection remain poorly understood. In this study, we delineate the stepwise differentiation trajectory of Th1 cells, tracing their progression from TCF-1hi progenitors through an intermediate state to fully differentiated Th1 cells. We identify an intermediate CD4+ T cell subset that serves as a precursor to Th1 cells, demonstrate that PD-1/PD-L1 signaling suppresses the transition from the progenitor to intermediate state, whereas the chromatin-remodeling complex PBAF restricts the terminal differentiation of CD4+ T cells into the Th1 subset. Notably, the combined blockade of PD-1/PD-L1 and genetic ablation of PBAF component (ARID2) additively enhanced Th1 differentiation and maintenance, leading to effective viral control. Thus, targeting these mechanisms driving CD4 Th1 cell differentiation and maintenance could enhance therapeutic strategies to restore Th1 function and control chronic infection.

Keywords:  CD4+ T cells; LCMV; Th1 differentiation; chromatin remodeling; immunotherapy

DOI:  https://doi.org/10.1073/pnas.2522928123
Cell Immunol. 2026 Feb 02. pii: S0008-8749(26)00005-5. [Epub ahead of print]419 105065

Ibrutinib enhances stem-cell-memory T cell generation during early T cell activation but inhibits T cell proliferation.

Ling He, Yifei Liu, Junjie Zhou, Taiyan Zhang, Shihao Zhang, Jian Ge, Jian Hong.

  Ibrutinib has been demonstrated to restore T cell immunity of chronic lymphocytic leukemia patients, and enhance ex vivo expansion and function of CAR-T cells. In attempt to explore the effect of ibrutinib on unmanipulated T cells, we activated human PBMCs from healthy donors with CD3/CD28 stimulation and cultured them with or without ibrutinib under various conditions. Phenotypic and functional assessments were then performed using flow cytometry. Results showed that ibrutinib could downregulate programmed cell death protein 1 expression and reduce activation-induced cell death of T cells. Additionally, ibrutinib added at the onset of T cell activation, rather than 48 h later, could further promote the generation of CD45RA+CCR7+CD95+ stem-cell-memory T cell subset in the presence of IL-7 and IL-15. However, ibrutinib also suppressed the proliferation and cytokine-secretion capacity of T cells in a dose-dependent manner. Further RNA sequencing of activated CD8+ T cells demonstrated that ibrutinib administration at the onset of T cell activation modulated multiple TCR downstream signaling pathways, notably downregulating mTORC1 signaling and upregulating FOXO1 signaling. In contrast, ibrutinib added 48 h post-activation did not show these effects. These findings suggest that caution should be exercised when incorporating ibrutinib into ex vivo expansion system for adoptive non-genetically engineered T cells or combining ibrutinib with these T cell immunotherapies in clinical trial settings.

Keywords:  Activation-induced cell death; Cytokine-secretion capacity; Ibrutinib; Proliferation; T cell; Tscm cell phenotype

DOI:  https://doi.org/10.1016/j.cellimm.2026.105065
Immunity. 2026 Jan 30. pii: S1074-7613(26)00038-5. [Epub ahead of print]

Targeting immune cells in the aged brain reveals that engineered cytokine IL-10 enhances neurogenesis and improves cognition.

Paloma Navarro Negredo, Justin You, Max Hauptschein, Adam B Schroer, Daniel J Richard, Gita C Abhiraman, Andy P Tsai, Eric D Sun, Giulia Notarangelo, Julliana Ramirez-Matias, Olivia Y Zhou, Matthew T Buckley, Karen E Malacon, Lucy Xu, Juliana Sucharov, Eduardo Ramirez Lopez, Lora Picton, Tony Wyss-Coray, Robert A Saxton, Ricardo A Fernandes, Saul A Villeda, K Christopher Garcia, Anne Brunet.

  The immune system could play an important role in the age-related decline in brain function, yet specific immune-based strategies to enhance brain resilience in older individuals are lacking. Here, we combined engineered proteins and direct brain delivery to target immune cell populations within the old brain. We detected T cells with an exhaustion signature in the old brain and targeted them with a potent engineered checkpoint inhibitor (RIPR-PD1). This led to T cell expansion and strong pro-inflammatory responses in many brain cell types, notably microglia. To rescue age-related inflammatory imbalances in microglia, we used the anti-inflammatory cytokine interleukin (IL)-10. IL-10 boosted anti-inflammatory responses in old microglia, but it also triggered pro-inflammatory signaling. An engineered IL-10 variant that uncouples pro- and anti-inflammatory responses positively impacted the transcriptome of multiple cell types, enhanced neurogenesis, and improved cognition in aged mice. Our findings pave the way for immunotherapies for the aged brain.

Keywords:  T cells; brain aging; checkpoint inhibitors; engineered proteins; inflammation; interleukin-10; microglia; neuro-immune interactions; neurogenesis; single-cell RNA sequencing

DOI:  https://doi.org/10.1016/j.immuni.2026.01.016
Mech Ageing Dev. 2026 Feb 02. pii: S0047-6374(26)00012-6. [Epub ahead of print]230 112160

Mechanistic insights into stem cell aging: Pathways and processes.

Ayesha Fauzi, Chloe Zi En Wong, Phoebe Yon Ern Tee, Ashlyn Wen Ning Yau, Elisha Ab Rashid, Yin Quan Tang, Adeline Yoke Yin Chia.

  Aging progressively alters stem cell function, undermining tissue homeostasis and contributing to age-related diseases. This review synthesises current evidence on the molecular and cellular mechanisms that drive stem cell aging, with emphasis on cellular stress responses, epigenetic regulation, telomere dynamics, metabolic control, and signalling pathway dysregulation. Accumulation of oxidative, genotoxic, and endoplasmic reticulum stress with age disrupts genomic stability and proteostasis, impairing self-renewal and regenerative capacity and, in specific contexts, promoting cellular senescence. Age-associated epigenetic alterations, including DNA methylation drift, histone modification changes, and chromatin remodelling defects, destabilise transcriptional programs required for stem cell quiescence, lineage commitment, and identity maintenance. Telomere shortening, driven by replicative history and oxidative damage, limits proliferation and induces DNA damage signalling. Senescence-associated secretory signalling affects its environments, disrupting stem cell niches and amplifying functional decline. Aging also perturbs nutrient- and energy-sensing pathways such as mTOR and AMPK, leading to impaired autophagy, mitochondrial dysfunction, and metabolic inflexibility. These signalling changes are accompanied by shifts in cellular metabolism and increased oxidative burden. Collectively, these mechanisms impair stem cell maintenance, differentiation capacity, and regenerative output. By integrating these processes, this review provides a framework for identifying regulatory targets relevant to preserving stem cell function in aging tissues.

Keywords:  Aging; DNA methylation; Epigenetic dysregulation; Senescence; Stem cell

DOI:  https://doi.org/10.1016/j.mad.2026.112160
bioRxiv. 2026 Jan 20. pii: 2026.01.15.697975. [Epub ahead of print]

Macrophage immunosenescence prolongs intraocular inflammation in aged mice via impaired induction of regulatory T cells.

Taku Yamamoto, Keitaro Hase, Joseph B Lin, Shinobu Yamaguchi, Norihiko Misawa, Jiayi Li, Kenta Kato, Ryo Terao, Brian S Sohn, Daniel Du, Mitsukuni Yoshida, Charles W Pfeifer, Tae Jun Lee, Jason Colasanti, Andrea Santeford, James T Walsh, Rajendra S Apte.

Immune-mediated intraocular inflammation, called uveitis, is a leading cause of global blindness, with the highest burden of visual impairment falling on older individuals. Immunosenescence, the functional changes in immune cells with aging, impacts the age-associated immune response, but how immunosenescence and the molecular regulators of the age-associated immune response affect the clinical course of uveitis remains unclear. In the murine model of experimental autoimmune uveitis (EAU), aged mice demonstrated a delayed onset and peak of intraocular inflammation compared to young mice. In contrast to the canonical monophasic inflammation that rapidly resolves in young mice, aged mice developed persistent, chronic inflammation. Transcriptomic and flow-cytometric analyses of immune cells and the receptor-ligand interactome revealed a dominant macrophage-CD4 + T cell signature. This signaling pathway was functionally altered on both ends: macrophages from aged mice had an impaired capacity to generate peripherally induced regulatory T cells (pTreg) through an IL-6 regulated pathway, while CD4 + T cells co-cultured with aged macrophages demonstrated increased proliferation. Our study establishes aging as a key regulator of the effector immune response in uveitis. Regulatory T cells, specifically pTreg, are essential for resolving inflammation in uveitis and an impaired ability to induce pTreg led to a sustained, chronic inflammatory uveitis phenotype in old mice, thereby linking immunosenescence to persistent neuroinflammation. These findings highlight potential therapeutic avenues for vision-threatening uveitis, especially in older patients.

DOI: https://doi.org/10.64898/2026.01.15.697975
Ageing Res Rev. 2026 Jan 28. pii: S1568-1637(26)00031-0. [Epub ahead of print]115 103039

Ageing and liver immune cells.

Jarrod J Kennedy, Patrick Bertolino, Sophie Lucic Fisher, Meng C Ngu, Nicholas J Hunt, Peter A G McCourt, Victoria C Cogger, David G Le Couteur.

  Ageing is associated with a dysregulated immune system that contributes to vulnerability in older adults to infection, malignancies, autoimmune diseases, and inflammatory disorders. This immune dysfunction can be categorised into two processes: progressive decline in immune responsiveness (immunosenescence) and chronic low-grade systemic inflammation (inflammaging). These processes perpetuate a cycle wherein persistent inflammation accelerates immune cell exhaustion and senescence, while diminished immune surveillance heightens inflammation, together promoting tissue damage and age-related disease. The liver, a crucial immune organ pivotal for maintaining systemic immune tolerance, assumes an increasingly prominent role in regulating peripheral immune tolerance as age-related thymic involution diminishes central tolerance. Ageing alters the liver's immune landscape, with diverse patterns of infiltration and structural remodelling marked by the emergence of ageing-related tertiary lymphoid-associated structures (ATLAS), enriched with focal clusters of inflammatory cells. These structures and associated fibrotic niches function as hubs for pro-inflammatory and pro-fibrotic signalling. Transcriptomic studies reveal consistent upregulation of inflammatory immune pathways and pro-inflammatory cytokines across the aged liver. Immune cells are dysregulated with liver macrophages shifting toward pro-inflammatory phenotypes, NK cells showing exhaustion with reduction in frequency and impaired senescent cell clearance. T and B cells accumulate exhausted phenotypes with expanding populations of senescence-associated T cells (SATs) and age-associated B cells (ABCs), respectively. Liver sinusoidal endothelial cells (LSECs) undergo pseudo-capillarization and defenestration, creating a physical barrier that impairs clearance of tissue-adjacent T cells by hepatocytes. Taken together, age-related immune changes in liver immune cells indicate that the liver plays a central role in systemic inflammation in old age.

Keywords:  Ageing; Immunology; Immunosenescence; Inflammaging; Liver; Senescence

DOI:  https://doi.org/10.1016/j.arr.2026.103039
Nat Commun. 2026 Jan 30.

Clonal expansion of cytotoxic CD8⁺ T cells in lecanemab-associated ARIA.

Lance A Johnson, Kai Saito, Akhil V Pallerla, Jessica L Funnell, Ashley R Ezzo, Chelsea M Song, Douglas A Harrison, Noah J Norton, Lauren C Moore, Linda J Van Eldik, David W Fardo, Greg E Cooper, Josh M Morganti.

Amyloid-related imaging abnormalities (ARIA) are the principal safety concern limiting anti-amyloid therapies for Alzheimer's disease, yet their biology remains unclear. Here we show, through multi-omic profiling of peripheral blood from three ARIA+ patients and matched controls, that ARIA is associated with coordinated reprogramming of CD8 + T cells. CD8+ effector memory (TEM) and terminally differentiated (TEMRA) subsets were expanded, clonally enriched, and transcriptionally primed for cytotoxicity and vascular trafficking. Transcription factor inference and metabolomics converged on glycolytic reprogramming favoring short-lived effector function. Ligand-receptor modeling revealed enhanced monocyte-to-T cell signaling through antigen presentation, adhesion, and chemokine axes, while integration with a cerebrovascular atlas confirmed that ARIA-associated TEMRAs are transcriptionally "addressed" for vascular engagement. Together, these findings identify a peripheral immune signature linking metabolic reprogramming, clonal CD8+ expansion, and altered intercellular communication to ARIA, with implications for biomarker development and risk mitigation pending validation in larger cohorts.

DOI: https://doi.org/10.1038/s41467-026-68921-3
Nature. 2026 Feb 04.

Atlas-guided discovery of transcription factors for T cell programming.

H Kay Chung, Cong Liu, Anamika Battu, Alexander N Jambor, Brandon M Pratt, Fucong Xie, Brian P Riesenberg, Eduardo Casillas, Ming Sun, Elisa Landoni, Yanpei Li, Qidang Ye, Daniel Joo, Jarred Green, Zaid Syed, Nolan J Brown, Matthew Smith, Shixin Ma, Shirong Tan, Brent Chick, Victoria Tripple, Z Audrey Wang, Jun Wang, Bryan Mcdonald, Peixiang He, Qiyuan Yang, Timothy Chen, Siva Karthik Varanasi, Michael LaPorte, Thomas H Mann, Dan Chen, Filipe Hoffmann, Josephine Ho, Jennifer Modliszewski, April Williams, Yusha Liu, Zhen Wang, Jieyuan Liu, Yiming Gao, Zhiting Hu, Ukrae H Cho, Longwei Liu, Yingxiao Wang, Diana C Hargreaves, Gianpietro Dotti, Barbara Savoldo, Jessica E Thaxton, J Justin Milner, Susan M Kaech, Wei Wang.

CD8+ T cells differentiate into diverse states that shape immune outcomes in cancer and chronic infection1-4. To define systematically the transcription factors (TFs) driving these states, we built a comprehensive atlas integrating transcriptional and epigenetic data across nine CD8+ T cell states and inferred TF activity profiles. Our analysis catalogued TF activity fingerprints, uncovering regulatory mechanisms governing selective cell state differentiation. Leveraging this platform, we focused on two transcriptionally similar but functionally opposing states that are critical in tumour and viral contexts: terminally exhausted T (TEXterm) cells, which are dysfunctional5-8, and tissue-resident memory T (TRM) cells, which are protective9-13. Global TF community analysis revealed distinct biological pathways and TF-driven networks underlying protective versus dysfunctional states. Through in vivo CRISPR screening integrated with single-cell RNA sequencing (in vivo Perturb-seq) we delineated several TFs that selectively govern TEXterm cell differentiation. We also identified HIC1 and GFI1 as shared regulators of TEXterm and TRM cell differentiation and KLF6 as a unique regulator of TRM cells. We discovered new TEXterm-selective TFs, including ZSCAN20 and JDP2, with no previous known function in T cells. Targeted deletion of these TFs enhanced tumour control and synergized with immune checkpoint blockade but did not interfere with TRM cell formation. Consistently, their depletion in human T cells reduces the expression of inhibitory receptors and improves effector function. By decoupling exhaustion TEX-selective from protective TRM cell programmes, our platform enables more precise engineering of T cell states, accelerating the rational design of more effective cellular immunotherapies.

DOI: https://doi.org/10.1038/s41586-025-09989-7
iScience. 2026 Feb 20. 29(2): 114612

CD4+ to CD8+ T cell imbalance drives poor Achilles tendon repair in patients.

Franka Klatte-Schulz, Sven Geißler, Nicole Bormann, Susann Minkwitz, Serafim Tsitsilonis, Sebastian Manegold, Tobias Gehlen, Josephine A Melzer, Alper Kurtoglu, Aysha Bonell, Katharina Schmidt-Bleek, Georg N Duda, Birgit Sawitzki, Britt Wildemann.

  Insufficient healing of the Achilles tendon remains a frequent clinical challenge, creating a need for early markers that identify patients at risk of impaired healing. To examine whether adaptive immunity contributes to these outcomes, we analyzed T cell subsets in blood and hematoma collected during surgery. Patients with a higher CD4+/CD8+ T cell ratio at surgery reported more pain, showed reduced functional recovery, and greater tendon strain after 12 months. Conversely, elevated CD8+ T cell levels, and the CD28-/CD57+ memory subset, coincided with more favorable outcomes. We then investigated how these cells affect tendon healing by co-culturing human tenocytes with CD4+ or CD8+ T cells. Exposure to CD4+ T cells increased collagen type 3, IL-17 receptors and matrix metalloproteinases expression, indicating a shift toward impaired extracellular matrix organization. These results suggest that the CD4+/CD8+ T cell balance may serve as a prognostic marker and that modulating CD4+ T cell activity or IL-17 signaling could improve tendon repair.

Keywords:  Cell biology; Immunology

DOI:  https://doi.org/10.1016/j.isci.2025.114612
Methods Cell Biol. 2026 ;pii: S0091-679X(25)00101-3. [Epub ahead of print]201 91-107

Mouse and human T cell Cas9-RNP/nucleofection-mediated gene-editing.

Moah Sohn, Gvantsa Pantsulaia, Joshua Brody.

  CRISPR/Cas9 technology has revolutionized genome editing, providing a precise and expeditious means of genetic modification. This breakthrough has enhanced our understanding of gene function, including T cell immunology. Efficient gene editing in primary T cells not only offers a robust investigative tool for dissecting gene function but also holds promise for advancing T cell-based immunotherapies, including next-generation chimeric antigen receptor T cells. In this article, we introduce a highly efficient gene editing protocol for unstimulated human CD8 T cells and unstimulated and stimulated murine CD8 T cells, utilizing transient nucleofection of ribonucleoprotein complexes composed of synthesized modified single guide RNAs (sgRNAs) and purified Cas9 protein. This protocol, initially devised for primary CD8 T cells, can be readily adapted to other primary cell cultures through optimization of nucleofection conditions as well. In essence, our method provides a practical and powerful approach for achieving precise and swift gene knockout in primary CD8 T cells.

Keywords:  CD8 T cell; CRISPR; Gene editing; Knockout; T cell

DOI:  https://doi.org/10.1016/bs.mcb.2025.03.020
Nat Commun. 2026 Feb 05.

Tumour-intrinsic features shape T cell differentiation through precursor to symptomatic multiple myeloma.

Kane A Foster, Elise Rees, Louise Ainley, Annabel Laidler, Eileen M Boyle, Lydia Lee, Gwennan Ward, Daria Galas-Filipowicz, Evelyn Fitzsimons, Anna Mikolajczak, Emma J Lyon, Dylan Jankovic, Jasmine Rahman, Mahima Turakhia, Dipal Mehta, Conor Garrod-Ketchley, Imran Uddin, Gordon Beattie, Yvette Hoade, Catherine Zhu, James L Reading, Ieuan Walker, Michael Chapman, Karthik Ramasamy, Javier Herrero, Benny Chain, Sergio A Quezada, Kwee L Yong.

Multiple myeloma (MM) is associated with skewed T cell activation and function which is present in asymptomatic myeloma precursor conditions, but underlying mechanisms of progression remain undefined. Here, we assemble a large single-cell RNA sequencing dataset of the bone marrow and blood from patients with MM, precursor conditions, and non-cancer controls. We demonstrate that, unlike solid cancers, MM is not characterized by T cell exhaustion, but by antigen-driven terminal memory differentiation. This is influenced by tumour-intrinsic features including tumour burden and expression of antigen-presentation genes. Expanded TCR clones accumulating in MM are not enriched with viral specificities but accumulate in effector states in highly-infiltrated marrows. Additionally, we identify a role for T cell dynamics in patients treated with autologous stem cell transplantation and demonstrate T cell features predict progression from precursor to symptomatic MM. Together, these results suggest that anti-tumour immunity drives a distinctive form of cancer-associated T cell differentiation in MM.

DOI: https://doi.org/10.1038/s41467-026-68718-4
Oncogenesis. 2026 Feb 06.

Fatty acid uptake mediated by FABP4 promotes the formation of CD8+T cell senescence through lipid peroxidation in the adipocyte-rich microenvironment of Ovarian Cancer.

Chunyan Yu, Xin Li, Xiaolong Qian, Haoke Zhang, Xueying Li, Bo Wang, Mantong Li, Zixuan Liu, Wei Du, Siqi Chen, Yuqing Ouyang, Xiaofan Feng, Tianhui He, Zihe Liu, Haixia Wu, Xiaoyan Zheng, Junru Liu, Hong Zhang, Yuanming Song, Chenying Liu, Jiazhen Li, Hongyan Guo, Shiwen Xu, Xiaojing Guo, Weimin Deng.

T cell senescence significantly impairs the efficacy of immune checkpoint blockade (ICB) therapy in cancer. Metabolic reprogramming is a crucial factor in T cell senescence in tumor microenvironment (TME). Ovarian cancer (OvCa) patients derive limited benefit from ICB treatment, probably related to T cell senescence. OvCa cells metastasize to the abdominal cavity rich in omental fat and raise ascites, forming a unique TME, adipocyte-rich TME. In this study, we investigated the effects of adipocyte-rich TME on T cell senescence. Using the single-cell RNA sequencing of OvCa and clinical samples, we found that adipocyte-rich TME is strongly associated with the formation of senescence CD8+T (CD8+Tsen) cells. Mechanistically, adipocyte-derived factors (MATES) and oleic acid (OA)-the predominant fatty acid in OvCa ascites-promoted tumor-induced CD8+Tsen formation by enhancing fatty acid (FA) uptake via FABP4, triggering lipid peroxidation rather than energy production. Inhibition of FABP4 (using the inhibitor BMS309403 or siRNA knockdown) blocked CD8+Tsen cell formation, reduced lipid peroxidation, restored CD8+T cell effector function, and suppressed immunosuppressive cytokines. Moreover, using an OvCa mouse model, we found that in OvCa mice BMS309403 treatment partially diminished CD8+Tsen formation by reducing FA uptake, and improved anti-tumor immunity, and prolonged the survival time of OvCa mice when combined with chemotherapy. Our work suggests FABP4-mediated FA metabolism as a therapeutic target to counteract T cell senescence in adipocyte-rich TME, providing a novel immunotherapeutic strategy for OvCa.

DOI: https://doi.org/10.1038/s41389-026-00600-w
Int Immunopharmacol. 2026 Feb 04. pii: S1567-5769(26)00145-1. [Epub ahead of print]173 116302

Polysialylated CD56 drives immune evasion in clear cell renal cell carcinoma via engagement of the Siglec-7 checkpoint on CD8+ T cells.

Yuli Jian, Li Gong, Ling Tang, Moyuan Zhang, Shiya You, Zhilin Li, Mingxin Wu, Shuang Wang, Zheng Zhu, Deyong Yang, Shujing Wang.

  Immune checkpoint blockade has revolutionized clear cell renal cell carcinoma (ccRCC) treatment, yet therapeutic resistance remains a significant clinical challenge. Aberrant glycosylation contributes to tumor progression and immunotherapy resistance. However, the specific glycans and corresponding immunomodulatory receptors involved in ccRCC remain poorly understood. Here, we identify polysialylated CD56 (PSA-CD56) as a key glycan-mediated immune regulator that drives immunosuppression in ccRCC through engagement of Siglec-7. Elevated PSA-CD56 expression was inversely correlated with CD8+ T cell infiltration and predicted inferior responses to immunotherapy. Genetic ablation of NCAM1 (encoding CD56) in renal epithelial cells suppressed tumor growth and enhanced CD4+ and CD8+ T cell infiltration in vivo. Mechanistically, PSA-CD56, but not its non-polysialylated form, directly bound to Siglec-7 on CD8+ T cells, suppressing the production of IFN-γ and TNF-α and promoting T cell apoptosis. Importantly, blocking the PSA-CD56/Siglec-7 interaction with specific antibodies restored T cell effector functions and triggered apoptosis of ccRCC cells. Our study unveils the PSA-CD56/Siglec-7 axis as a novel glyco-immune checkpoint, which represents a promising target for therapeutic interventions in ccRCC.

Keywords:  Cell apoptosis; Clear cell renal cell carcinoma; Immune evasion; PSA-CD56; Siglec-7

DOI:  https://doi.org/10.1016/j.intimp.2026.116302