bims-imseme 2026-02-01 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2026–02–01
twenty-six papers selected by
Pierpaolo Ginefra, Ludwig Institute for Cancer Research

CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.
CARM1-mediated hypoxanthine-enriched exosomes rewire inosine metabolism and impair CD8+ T cell antitumor function.
Metabolic traits of T cells and the implications in autoimmune diseases.
CD8a antibody-functionalized biomimetic red blood cell membrane ectosomes delivering C646 reverse CD8⁺ T Cell exhaustion via H3K18la histone delactylation in gastric cardia adenocarcinoma.
SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling.
Recapitulating the qualities of HIV-specific CD8+ T cells from spontaneous controllers.
Portrayed the development of activated T cell to exhausted T cell based on the ratio of CD28 to CTLA4.
CAR Intrinsic Design Pre-Shapes Transcriptional and Metabolic Networks in CAR T Cells.
Terminally exhausted CD8+ T cells in solid tumors: biology, biomarker potential and translational tools for precision oncology.
Loss of SOCS1 in Donor T Cells Exacerbates Intestinal GVHD by Driving a Chemokine-Dependent Pro-Inflammatory Immune Microenvironment.
ARTN drives CD8+ T cell exhaustion via the GFRα3-RET-PI3K/AKT Axis to promote TNBC progression.
Editorial: Epigenetic regulation of T cell function in type 1 diabetes.
Type I interferon drives dysfunction of a distinct CD8+ HLA-DRB1+ T cell subset in systemic lupus erythematosus.
RBM15/IGF2BP3 promotes immune escape in bladder cancer by enhancing m6A modification of PFKFB4.
Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy.
METTL3/CD98-mediated glutamate efflux in CAFs drives CD8+ T cell exhaustion and impedes neoadjuvant immunochemotherapy.
IL-2 Free Expansion of T Cells with Immunofilaments.
CD82-associated exhausted CD8+ T cells define prognosis and immunotherapy resistance in colon cancer.
Coordination of cell organelles to promote metabolon formation.
Targeting Pim2 Improves Antitumor Immunity through Promoting Effector Function and Persistence of CD8 T cells.
Enhancing Adoptive T Cell Therapy by Disrupting the SKI-SMAD2/3 Axis to Counteract TGF-β-Mediated Immunosuppression.
Frontiers of cytokine engineering in CAR cell therapy for cancer.
Loss of LXRβ Drives CD4+ T Cell Senescence and Exacerbates the Progression of Colitis.
Empowering exhausted T cells of Glioblastoma patients by Neurotransmitters and Neuropeptides: decreasing immune checkpoint inhibitors, and increasing CD3zeta, proliferation and Glioblastoma arrest.
A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.
Activated CD38+ mast cells promote gastric cancer progression by suppressing CD8+ T cell cytotoxic activity through adenosine metabolism.

bioRxiv. 2026 Jan 24. pii: 2026.01.22.701075. [Epub ahead of print]

CRISPR screens identify targets to rescue age-related T cell dysfunction in cancer.

Alex C Y Chen, Keely Y Ji, Cansu Yerinde, Nelson H Knudsen, Kevin Bi, Daniela Martinez, Thomas J Carmona-LaSalle, Kazuhiro Taguchi, Katherine H Xu, Elizabeth M Seider, Marc A Schwartz, Maria Zschummel, Linda T Nieman, Kathleen B Yates, Thorsten R Mempel, Robert T Manguso, Nir Hacohen, Debattama R Sen.

Immune aging is being increasingly recognized as a critical barrier to effective cancer immunotherapy, as the aged tumor microenvironment (TME) drives T cell dysfunction and impairs immune control of cancer. However, the key molecular drivers of this process as well as potential targets to rescue T cell dysfunction in aged tumors remain incompletely understood. Therefore, we performed in vivo single-cell CRISPR screens in CD8 + T cells within aged tumors and tumor-draining lymph nodes (tdLNs). We identified Dusp5 and Zfp219 as key regulators of T cell persistence and effector differentiation in aged hosts. Loss of Dusp5 , a negative regulator of ERK signaling, increased ERK1/2 phosphorylation and enhanced T cell proliferation in both young and aged tumors. In contrast, loss of Zfp219 , a transcriptional repressor, induced epigenetic reprogramming of cytotoxic gene programs, thereby increasing granzyme secretion and enhancing antitumor immunity. Moreover, expression of the human ortholog gene ZNF219 is increased within intratumoral CD8 + T cells in older cancer patients. High ZNF219 expression correlates with poorer survival following immune checkpoint blockade (ICB) and reduces persistence of human intratumoral T cells. Notably, Zfp219 ablation synergized with anti-PD-1 blockade in mice to expand effector-like CD8 + T cells, leading to significantly enhanced anti-tumor immunity and tumor clearance in aged hosts. Together, these findings highlight Dusp5 and Zfp219 as critical drivers of age-related T cell dysfunction and as potential therapeutic targets to rejuvenate T cell antitumor immunity in older cancer patients.

DOI: https://doi.org/10.64898/2026.01.22.701075
Cell Death Differ. 2026 Jan 24.

CARM1-mediated hypoxanthine-enriched exosomes rewire inosine metabolism and impair CD8+ T cell antitumor function.

Jilong Yin, Zhipeng Su, Xi Hu, Haojie Sun, Zenghui Sun, Shuyu Zhou, Wenwen Xu, Ying Xi, Lanlan Liu, Jinwei Zhang, Qian Zhao, Yi Qiao, Jian Zhang, Yingjie Zhang, Ying Xu, Yuchen Fan, Xiaona You, Xiangbo Meng, Fabao Liu.

Cancer cells utilize tumor-derived exosomes to suppress antitumor immunity. Herein, we identify co-activator-associated arginine methyltransferase 1 (CARM1) as a key regulator of exosome biogenesis and metabolite sorting that inhibiting CD8+ T cell-mediated antitumor responses. Genetic ablation of CARM1 in breast cancer cells impairs immunosuppressive exosome secretion, enhancing CD8+ T cell infiltration, proliferation, and effector function. Mechanistically, CARM1 dimethylates apoptosis-linked gene-2 interacting protein X (ALIX) at arginine 757, facilitating its interaction with endosomal sorting complex required transport (ESCRT) components, and promoting tetraspanin-enriched exosome biogenesis. CARM1-dependent ALIX methylation enables selective packaging hypoxanthine into exosomes through direct binding to the ALIX F676 pocket. Exosomal hypoxanthine disrupts inosine metabolism in activated CD8+ T cells, inhibiting pentose phosphate pathway, glycolysis, nucleotide synthesis, and effector cytokine production. Co-administration of CARM1 inhibitor with inosine significantly enhances tumor-infiltrating CD8+ T cell cytotoxicity, reduces PD-1+TIM-3+ exhausted CD8+ T cells, and suppresses tumor growth. These findings establish the CARM1-ALIX-hypoxanthine axis as an immunosuppressive mechanism and suggest that combining CARM1 inhibition with inosine supplementation represent a promising therapeutic strategy for breast cancer.

DOI: https://doi.org/10.1038/s41418-026-01673-1
Autoimmun Rev. 2026 Jan 22. pii: S1568-9972(26)00003-0. [Epub ahead of print]25(2): 103989

Metabolic traits of T cells and the implications in autoimmune diseases.

Yi Zhou, Yuqi Zhou, Qing Zhu, Weinan Guo, Chunying Li.

  The metabolic activities of T cells play a pivotal role in regulating their activation, differentiation, and effector functions. In recent years, it has emerged as a key focus of research in the maintenance of immune homeostasis and the modulation of inflammatory responses. T cells not only rely on metabolic reprogramming to meet their energy and biosynthesis demands, but also utilize intermediate metabolites to regulate epigenetic modifications and then affect gene expression and cell fate. More importantly, T cell metabolism faces adaptive pressures in tissue-specific microenvironments, which impact their effector capabilities and participate in immune tolerance maintenance. Currently, traditional immunosuppressive therapy still has limitations in the treatment of autoimmune diseases, with notable side effects. Meanwhile, targeting T cell metabolism, as an emerging strategy for intervening in autoimmune responses, has demonstrated promising potential in multiple research studies. This review provides a comprehensive overview of the metabolic characteristics of T cells at different developmental stages and functional states, explores the interactive mechanisms between metabolism and epigenetic regulation in T cells, and discusses the influence of tissue microenvironments on T cell metabolic behavior. Finally, we highlighted recent advancements in targeting T cell metabolism for treating systemic lupus erythematosus, psoriasis, inflammatory bowel disease, and multiple sclerosis. This provides new directions for developing precise clinical intervention strategies for patients with autoimmune diseases.

Keywords:  Autoimmune diseases; Immunometabolism; Metabolism; T cells

DOI:  https://doi.org/10.1016/j.autrev.2026.103989
J Nanobiotechnology. 2026 Jan 29.

CD8a antibody-functionalized biomimetic red blood cell membrane ectosomes delivering C646 reverse CD8⁺ T Cell exhaustion via H3K18la histone delactylation in gastric cardia adenocarcinoma.

Zheng Xiang, Xinxin Zhang, Xinlei Liu, Xiaohu Lv, Yubo Hu, Chi Zhang, Chunlei Zou, Anqi Wang, Bo Zhang, Wei Wang, Guodong Cao, Jianguang Jia.

  The functional exhaustion of CD8+ T cells in the tumor microenvironment (TME) severely limits anti-tumor immunity in gastric cardia adenocarcinoma (GCA). Here, we developed CD8a antibody-functionalized biomimetic red blood cell membrane ectosomes (CD8a-NVEs) encapsulating the p300 inhibitor C646 to selectively target and reprogram exhausted CD8+ T cells. Single-cell RNA sequencing of human GCA tissues revealed lactate-driven epigenetic remodeling, characterized by elevated H3K18 lactylation (H3K18la) at the PDCD1 promoter, which correlated with impaired CD8⁺ T cell function. In vitro, C646 effectively reduced H3K18la, suppressed PDCD1 transcription, and restored effector molecule expression, including IFN-γ and GZMB. CD8a-NVEs@C646 exhibited superior targeting specificity, biocompatibility, and functional efficacy, markedly enhancing CD8⁺ T cell proliferation and cytotoxicity compared with free C646. In a humanized orthotopic GCA model, CD8a-NVEs@C646 significantly inhibited tumor growth, and its combination with anti-PD-1 therapy further enhanced T cell infiltration and tumor apoptosis. This biomimetic nanoplatform enables precise epigenetic reprogramming of tumor-infiltrating CD8⁺ T cells, overcoming lactate-induced histone modifications and reversing exhaustion. Collectively, these findings present a translational nanobiotechnology-based strategy to potentiate immunotherapy efficacy in GCA and potentially other malignancies driven by T cell dysfunction.

Keywords:  C646; Gastric cardia adenocarcinoma; H3K18la; Programmed cell death protein 1; Red blood cell membrane-derived ectosomes

DOI:  https://doi.org/10.1186/s12951-025-03957-z
Nat Immunol. 2026 Jan 29.

SIRT2-mediated deacetylation of LCK governs the magnitude of T cell receptor signaling.

Imene Hamaidi, Pingyan Cheng, Soo Young Jun, Alak Manna, Min-Hsuan Wang, Anh Nguyen, Ismail Can, Min G Zhang, Odesha O Taylor, Luis Uriel Lopez Bailon, Bin Fang, Bradford Perez, Ben C Creelan, Andriy Marusyk, Dongjun Shin, Tae Hyun Hwang, Anders E Berglund, Virginia S Shapiro, Haitao M Ji, José R Conejo-Garcia, Sungjune Kim.

T cell receptor (TCR) signaling is precisely tuned to prevent self-reactivity while allowing protective immunity. Here we found that acetylation modulated TCR signaling. The loss of SIRT2 deacetylase activity in T cells led to amplified calcium mobilization and phosphorylation of key proximal TCR molecules in naive T cells and reversed dampened TCR signaling in anergic T cells. During thymic selection, SIRT2 deficiency lowered the TCR signaling threshold and resulted in a broader TCR repertoire diversity. Mechanistically, we identified acetyl-lysine K228 on the linker region of LCK as a substrate specific for SIRT2 that governed LCK conformation and activity. SIRT2 inhibition in exhausted mouse and human tumor-infiltrating T cells restored TCR responsiveness and antitumor immunity. These findings highlighted SIRT2-modulated protein acetylation as a regulatory mechanism that set the TCR threshold in T cells.

DOI: https://doi.org/10.1038/s41590-025-02377-3
Curr Opin HIV AIDS. 2026 Jan 29.

Recapitulating the qualities of HIV-specific CD8+ T cells from spontaneous controllers.

Karla DeLucas, Joel N Blankson, Rachel L Rutishauser.

   PURPOSE: Studies in spontaneous controllers of HIV and, more recently, post-treatment controllers have shown that effective HIV-specific CD8+ T cell responses may mediate control of the virus in the absence of antiretroviral therapy. The purpose of this review is to first discuss the unique features of HIV-specific CD8+ T cells in spontaneous controllers. We will then explore how qualities of these cells might be harnessed using T cell engineering strategies.
SUMMARY OF RECENT FINDINGS: Several recent studies have deepened our understanding of HIV-specific CD8+ T cell responses in spontaneous controllers. These have included studies elucidating mechanisms by which preferential antigen restriction, specificity, sensitivity, and breadth promote enhanced T cell responses in spontaneous controllers, as well as studies demonstrating that manipulating the differentiation state or localization of HIV-specific T cells might alter their ability to control the virus. In parallel, many recently-developed approaches to engineer anti-cancer T cells could be used to recapitulate key properties of HIV-specific CD8+ T cells from spontaneous controllers (e.g., sensitive antigen receptors, targeted recognition of evolutionarily conserved and/or mutationally constrained epitopes, T cell stem/memory-like functional capacity).
SUMMARY: We identify several opportunities to apply novel approaches being developed in immuno-oncology to enhance the function of engineered T cells for HIV.

Keywords:  CD8+ T cell; engineered T cell; spontaneous controller

DOI:  https://doi.org/10.1097/COH.0000000000001017
Cancer Immunol Immunother. 2026 Jan 27. 75(2): 46

Portrayed the development of activated T cell to exhausted T cell based on the ratio of CD28 to CTLA4.

Yuan Wang, Xinyue Mei, Jiaying Zhong, Junxiang Wang, Jinpeng Cao, Shaojiang Zheng, Defeng Qi, Zhongfang Wang.

  T cell exhaustion, to some extent, limits the clearance of viruses and tumor cells and accounts for the poor effectiveness of immune therapy. The generally accepted classification of exhausted T cells assigns them as progenitor and terminal statuses. However, the outcome of immune therapy benefits little from this classification. In this study, we constructed a new indicator with the ratio of CD28 to CTLA4 (ccRatio) to continuously characterize the development of T cell from activation to exhaustion. We showed that the ccRatio decreased as T cell exhaustion progressed. We also found that patients who benefitted from anti-CTLA4 treatment had a higher ccRatio value. In addition, by studying the genes that correlated with ccRatio, we found ccRatio is associated with T cell functions which is further confirmed in validation datasets. Furthermore, we found that transcription factor VDR can contribute to differentiation of T cell from activation to exhaustion. The establishment of ccRatio allows us to study T cell exhaustion in a continuous developmental perspective, which is conducive to understand the T cell differentiation and helped in improving existing immunotherapy methods.

Keywords:  CD28 costimulator; CTLA4 coinhibitor; T cell differentiation; T cell exhaustion

DOI:  https://doi.org/10.1007/s00262-025-04297-5
Metabolites. 2026 Jan 07. pii: 52. [Epub ahead of print]16(1):

CAR Intrinsic Design Pre-Shapes Transcriptional and Metabolic Networks in CAR T Cells.

Didem Agac Cobanoglu, Samantha Franklin, Yue Hu, Devon J Boland, Xiaotong Song.

   BACKGROUND/OBJECTIVES: Chimeric antigen receptor (CAR) T cells are a powerful cancer therapy, but their function depends heavily on internal signaling domains and metabolic adaptability. Most studies evaluate CAR behavior upon antigen exposure, yet intrinsic signaling properties may pre-program CAR T cell states even in the absence of stimulation. This study investigates how CAR design and metabolic support shape baseline transcriptional programs, focusing on tonic signaling and NF-κB-related pathways.
METHODS: We engineered CAR T cells targeting HER2 or GPC3 antigens, incorporating either 4-1BB or CD28 co-stimulatory domains, respectively. A subset of cells was further modified with adenosine deaminase 1 (ADA1) and CD26 to degrade extracellular adenosine and supply inosine, a metabolic strategy termed metabolic refueling (MR). Bulk RNA-seq was performed on resting T cells without antigen stimulation. We analyzed differential gene expression, gene set enrichment (GO, KEGG, Hallmarks), and transcription factor activity (DoRothEA) to assess the impact of CAR design and MR on T cell programming.
RESULTS: All CAR T cells exhibited activation of NF-κB-centered inflammatory programs at baseline, indicating tonic signaling. GPC3 CAR T cells showed stronger baseline activation than HER2 CAR T cells. Metabolic refueling amplified these programs without altering their directionality, enhancing inflammatory, survival, and effector modules. Transcription factor activity scores mirrored these trends, highlighting RELA, FOS, and STATs as key regulatory nodes.
CONCLUSIONS: CAR-intrinsic features, notably co-stimulatory domain choice, define the tonic NF-κB activation tone in resting CAR T cells. Metabolic refueling boosts these baseline states without overstimulation, suggesting it may be especially valuable for weaker CAR constructs. These findings provide a framework for tuning CAR T cell function through combinatorial design strategies targeting signaling and metabolism.

Keywords:  NF-kB; RNA-seq; chimeric antigen receptors; transcription

DOI:  https://doi.org/10.3390/metabo16010052
Front Immunol. 2025 ;16 1709852

Terminally exhausted CD8+ T cells in solid tumors: biology, biomarker potential and translational tools for precision oncology.

Xuejun Guo, Shuhan Ma, Jingwen Wang, Yilin Fu, Wenxue Ma.

  Terminally exhausted CD8+ T cells (Ttex) are emerging as clinically relevant immune subsets across solid tumors, marked by sustained inhibitory receptor expression, loss of TCF1, and limited proliferative capacity. Once considered functionally inert, Ttex are now recognized for their residual cytotoxic potential and strong associations with tumor immunogenicity, including microsatellite instability (MSI), high tumor mutational burden (TMB), and neoantigen load. Importantly, the prognostic significance of Ttex is highly tumor-context-dependent, shaped by stromal architecture, mutational burden, and progenitor Tpex availability. This review examines the biology, spatial localization, and prognostic value of Ttex, highlighting the Ttex/CD8+ ratio as a promising biomarker in cancers such as colorectal, lung, and esophageal carcinoma. We summarize recent advances in multiplex imaging, digital pathology, and AI-driven quantification that support the clinical integration of Ttex assessment. In addition, we discuss emerging therapeutic strategies targeting Ttex through immune checkpoint combinations, thymocyte selection-associated high mobility group box protein (TOX) and circRNA-mediated reprogramming, and exhaustion-resistant T cell engineering. Finally, we outline translational priorities including assay harmonization, functional validation, and longitudinal profiling to advance Ttex-based precision oncology.

Keywords:  T cell exhaustion; digital pathology; immunotherapy biomarkers; precision oncology; terminally exhausted CD8⁺ T cells; tumor microenvironment

DOI:  https://doi.org/10.3389/fimmu.2025.1709852
Adv Sci (Weinh). 2026 Jan 25. e13735

Loss of SOCS1 in Donor T Cells Exacerbates Intestinal GVHD by Driving a Chemokine-Dependent Pro-Inflammatory Immune Microenvironment.

Zhigui Wu, Bixia Wang, Xinya Jiang, Fangqing Zhang, Qianqian Huang, Xinyi Wu, Shuang Fan, Qi Zhang, Jingrui Zhou, Jianing Tang, Xiao-Dong Mo, Yu Wang, Ying-Jun Chang, Huidong Guo, Xiao-Jun Huang.

  Acute graft-versus-host disease (aGVHD) of the gastrointestinal tract is a frequent and often fatal complication of allogeneic hematopoietic stem cell transplantation. Suppressor of Cytokine Signaling 1 (SOCS1) is a key regulator of T cell pathogenicity, yet its role in aGVHD remains unclear. Using T cell-specific Socs1 knockout models, we show that Socs1 loss intrinsically drives pro-inflammatory T cell differentiation independent of antigen stimulation, with the strongest effects observed in CD8+ T cells. Mechanistically, Socs1 deficiency activates a STAT1/2-dependent transcriptional program, inducing Ccl5 expression, monocyte recruitment, and M1-like macrophage polarization in peripheral lymphoid organs at steady state. After transplantation, Socs1-deficient T cells display enhanced infiltration into intestinal crypts, accompanied by increased CD8+ T cell effector function, monocyte accumulation, and inflammatory macrophage polarization in target tissues. These changes promote tissue injury and impair regeneration, resulting in lethal aGVHD. Importantly, JAK1/2 inhibition with ruxolitinib reverses these pathogenic effects. Clinically, high SOCS1 expression in donor-derived CD8+ T cells correlates with reduced aGVHD incidence. Together, our findings identify SOCS1 as a predictive biomarker and a potential therapeutic target for personalized aGVHD prophylaxis.

Keywords:  bone marrow transplantation; cell migration; chemokines; gastrointestinal tract; intestinal T cells

DOI:  https://doi.org/10.1002/advs.202513735
Cell Signal. 2026 Jan 27. pii: S0898-6568(26)00047-1. [Epub ahead of print] 112397

ARTN drives CD8+ T cell exhaustion via the GFRα3-RET-PI3K/AKT Axis to promote TNBC progression.

Dongke Yan, Yongling Wang, Lei Zhang, Yu Li, Yanchao Gong, Hongbin Liu, Xiaobao Ma, Jingjie Pang.

   BACKGROUND: Triple-negative breast cancer (TNBC) is an aggressive subtype with limited therapies. CD8+ T cell exhaustion drives TNBC immune escape, but mechanisms remain unclear. Artemin (ARTN), a secreted protein overexpressed in cancers, its role in regulating CD8+ T cells in TNBC tumor microenvironment is unknown.
OBJECTIVE: To investigate whether ARTN promotes TNBC progression by inducing CD8+ T cell exhaustion and clarify the underlying molecular mechanisms.
METHODS: Bioinformatics analyzed ARTN expression/prognostic value in TNBC. In vitro, ARTN knockdown/overexpression TNBC cells were used with Transwell, flow cytometry, and co-culture assays. Co-IP, Western blot, and gene knockdown identified ARTN's receptor and signaling in CD8+ T cells. In vivo, BALB/c mouse xenografts and RET inhibitor intervention verified ARTN's function.
RESULTS: ARTN was highly expressed in TNBC and correlated with poor prognosis. It promoted TNBC cell proliferation/invasion, inhibited apoptosis, and induced CD8+ T cell exhaustion (upregulated PD-1/Tim-3, increased TGF-β/IL-10). Mechanistically, ARTN bound GFRα3-RET on CD8+ T cells, activating PI3K/AKT. GFRα3/RET knockdown or RET inhibitor reversed these effects in vitro and in vivo.
CONCLUSION: This is the first study revealing ARTN induces CD8+ T cell exhaustion via GFRα3-RET-PI3K/AKT axis, promoting TNBC immune escape and progression. The ARTN-RET axis is a key immunosuppressive pathway, providing a potential target for combined immunotherapies.

Keywords:  ARTN; CD8(+) T cell exhaustion; GFRα3-RET; PI3K/AKT signaling pathway; TNBC

DOI:  https://doi.org/10.1016/j.cellsig.2026.112397
Front Immunol. 2025 ;16 1773432

Editorial: Epigenetic regulation of T cell function in type 1 diabetes.

Ubaid Ullah Kalim, Giuseppina Emanuela Grieco.



Keywords:  T cells; epigenetics; lncRNA - long noncoding RNA; microRNA; type 1 diabetes

DOI:  https://doi.org/10.3389/fimmu.2025.1773432
medRxiv. 2026 Jan 03. pii: 2026.01.02.26343348. [Epub ahead of print]

Type I interferon drives dysfunction of a distinct CD8+ HLA-DRB1+ T cell subset in systemic lupus erythematosus.

Huizhong Long, Elio Carmona, Mikhail G Dozmorov, Amr H Sawalha.

Objective: Systemic lupus erythematosus (SLE) is characterized by persistent type I interferon (IFN) signaling and adaptive immune dysregulation. We previously identified hypomethylation of HLA-DRB1 and STAT1 in SLE CD8+ T cells, enabling aberrant IFN-driven HLA-DRB1 expression and expansion of a distinct CD8+ T cell subset. This study aimed to comprehensively characterize CD8+ HLA-DRB1+ T cells in lupus.
Methods: Peripheral blood CD8+ T cells from SLE patients and healthy controls were analyzed by flow cytometry to assess differentiation and effector functions. Single-cell RNA sequencing and TCR sequencing, with and without IFN-α stimulation, were used to assess transcriptional heterogeneity, exhaustion, senescence, and cytotoxicity.
Results: CD8+ HLA-DRB1+ T cells were enriched within effector memory and terminally differentiated CD8+ T cells and were significantly expanded within the effector memory compartment in SLE compared to healthy controls. These cells displayed paradoxical features of cytotoxic activation, proliferative potential, exhaustion, and senescence. Compared to healthy controls, lupus CD8+ HLA-DRB1+ T cells exhibited increased exhaustion, reduced cytotoxicity, and impaired viral defense pathways. IFN-α treatment enhanced IFN-γ responses in lupus CD8+ HLA-DRB1+ T cells and exacerbated exhaustion and senescence. Despite upregulation of cytotoxic gene expression, IFN-α reduced CD107a surface mobilization, indicating impaired degranulation. Analysis of lupus nephritis datasets revealed that most kidney-infiltrating CD8+ T cells express HLA-DRB1.
Conclusion: CD8+ HLA-DRB1+ T cells represent a cytotoxic yet dysfunctional effector memory population expanded in SLE. Type I IFN drives this paradoxical state by promoting exhaustion and impaired degranulation, highlighting a potential therapeutic axis in SLE.

DOI: https://doi.org/10.64898/2026.01.02.26343348
Int J Biol Macromol. 2026 Jan 22. pii: S0141-8130(26)00068-1. [Epub ahead of print] 150142

RBM15/IGF2BP3 promotes immune escape in bladder cancer by enhancing m6A modification of PFKFB4.

Mei Chen, Linlin Zheng, Denggao Huang, Shunlan Wang, Xiaohong Wen, Yuanhui Gao, Shufang Zhang.

  The role of N6-methyladenosine (m6A) in shaping the tumor microenvironment remains incompletely understood. Here, we investigated the function of the m6A writer RBM15 in bladder cancer (BC). Single-cell sequencing and spatial transcriptomics demonstrated that RBM15 is predominantly expressed in malignant epithelial cells and exerts oncogenic effects. Integrated m6A-seq and lactylation proteomics analyses indicated that RBM15 could regulate both glycolysis and immunity through m6A modification and lactylation. Mechanistically, RIP-qPCR, MeRIP-qPCR, proteomic profiling, luciferase reporter assays, RNA stability tests, and rescue experiments revealed that RBM15 increased m6A modification and stability of PFKFB4 mRNA. We also revealed that RBM15-mediated PFKFB4 mRNA activation relied on the IGF2BP3-dependent pathway. Downregulation of RBM15 and IGF2BP3 suppressed glycolysis while enhancing the anti-tumor potential of CD8+ T cells, whereas PFKFB4 overexpression reversed these effects, and vice versa. In vivo, silencing RBM15 with lipid nanoparticle (LNP)-delivered siRNA enhanced the efficacy of anti-PD1 therapy and increased CD8+ T cell infiltration. Collectively, our findings demonstrate that RBM15 stabilizes PFKFB4 expression in BC through an m6A-IGF2BP3-dependent mechanism and thus promotes the glycolysis and inhibits CD8+ T cell function. Targeting RBM15 sensitizes tumors to PD1 blockade and provides a promising therapeutic strategy for BC.

Keywords:  Bladder cancer; CD8(+) T cells; Glycolysis; Immunotherapy resistance; RBM15; m6A modification

DOI:  https://doi.org/10.1016/j.ijbiomac.2026.150142
Cancer Immunol Immunother. 2026 Jan 27. 75(2): 37

Unleashing CAR-T potential in solid tumors: overcoming intrinsic and extrinsic hurdles to improve therapy.

Zhiwei Zhang, Dawei Cui, Hao Wang, Liming Wu, Xia Liu.

  Chimeric antigen receptor (CAR) T cell therapy has shown transformative success in hematologic malignancies, yet its application in solid tumors remains limited by a combination of intrinsic and extrinsic barriers. Intrinsically, CAR-T cells face challenges such as CAR instability, T cell exhaustion, insufficient tumor infiltration, and poor persistence. Extrinsically, the tumor microenvironment (TME) acts as a formidable obstacle, with physical barriers, metabolic constraints, and immunosuppressive signals that dampen CAR-T cell function. Recent advancements in CAR transduction, genetic reprogramming, and combination therapies have revealed novel strategies to overcome these hurdles. This review explores cutting-edge innovations aimed at unleashing the full potential of CAR-T therapy in solid tumors, focusing on strategies that enhance CAR-T cell function and persistence while addressing the immunosuppressive TME. By examining both intrinsic and extrinsic factors, we provide a comprehensive framework for future research and clinical application to improve CAR-T therapy for solid tumor treatment.

Keywords:  CAR transduction; CAR-T cell; Combination therapy; Solid tumor; Tumor microenvironment

DOI:  https://doi.org/10.1007/s00262-025-04278-8
Cell Rep. 2026 Jan 28. pii: S2211-1247(26)00011-2. [Epub ahead of print]45(2): 116933

METTL3/CD98-mediated glutamate efflux in CAFs drives CD8+ T cell exhaustion and impedes neoadjuvant immunochemotherapy.

Chunyu Feng, Su-Ran Li, Xiaoshuai Xu, Zihan Dang, Zihan Jiang, Erhui Jiang, Zhengjun Shang.

  The role of neurotransmitters in suppressing anti-tumor immunity has garnered increasing attention. While glutamate has been extensively studied in neurological diseases, its potential role in regulating anti-tumor immunity, particularly in the context of neoadjuvant immunochemotherapy, remains underexplored. In this study, we find that glutamate levels are elevated in the plasma of head and neck squamous cell carcinoma (HNSCC) patients. The METTL3/m6A/CD98 axis in cancer-associated fibroblasts (CAFs) is a key driver of glutamate secretion. Glutamate induces CD8+ T cell exhaustion through SLC1A3 and impairs the formation of immune memory in secondary lymphoid structures. Additionally, glutamate promotes ferroptosis resistance in HNSCC. Notably, glutamate depletion enhances the efficacy of neoadjuvant immunochemotherapy. Our findings provide insights into how the METTL3/m6A/CD98 axis-mediated regulation of glutamate efflux may sensitize HNSCC to neoadjuvant immunochemotherapy.

Keywords:  CD8(+) T cell; CP: cancer; CP: immunology; METTL3; cancer-associated fibroblasts; glutamate; head and neck squamous cell carcinoma; neoadjuvant immunochemotherapy

DOI:  https://doi.org/10.1016/j.celrep.2026.116933
Adv Healthc Mater. 2026 Jan 24. e03766

IL-2 Free Expansion of T Cells with Immunofilaments.

Marjolein Schluck, Lea Weiss, René Classens, Carl G Figdor, Roel Hammink.

  Novel biomaterial-based cancer immunotherapeutic strategies, such as artificial antigen-presenting cells (aAPCs), focus on activating T cells through molecular cues presented on synthetic constructs aiming to improve T cell activation and direct differentiation. To meet these aims, aAPC designs that allow control over the ratio and density of the stimulatory signals are crucial. In this study, we used polyisocyanopeptide based immunofilaments (IF) as nanosized aAPCs to study the influence of ratio and density of αCD3 and αCD28 on T cell expansion and phenotype. We observed differences in T cell expansion, cytokine production, and effector phenotype, dependent on both the density and ratio. Interestingly, supplementation with 30 to 1000 U/mL IL-2 did not influence T cell expansion, cytokine production, or the effector phenotype of the optimal performing IFs. In contrast, IL-2 supplementation increased the number of terminal effector T cells, increased TIM3 expression, and significantly increased the levels of Tregs in the culture. Taken together, these results suggest that careful finetuning of the density and ratio of stimulatory antibodies on IFs can omit the need for IL-2 supplementation, which leads to a preferable phenotype. As such, our findings can be used to optimize T cell expansion protocols for ACT.

Keywords:  Interleukin‐2; T cells; adoptive cell transfer (ACT); artificial antigen‐presenting cells (aAPCs); ex vivo expansion

DOI:  https://doi.org/10.1002/adhm.202503766
Front Immunol. 2025 ;16 1731154

CD82-associated exhausted CD8+ T cells define prognosis and immunotherapy resistance in colon cancer.

Jingfeng Zhang, Hengwei Cui, Shaoxian Wu, Hongwei Shi, Haitao Wang, Jingting Jiang.

  The regulation of T cell exhaustion within the tumor microenvironment plays a pivotal role in shaping the immune response to cancer and determining the efficacy of immunotherapy. However, the molecular factors governing this process in colon cancer remain poorly understood. This study investigates the expression characteristics and functional significance of the transmembrane protein CD82 in the colon cancer immune microenvironment, with emphasis on its regulatory role in CD8+ T cell exhaustion and clinical outcomes. Publicly available transcriptomic datasets were integrated with multiplex immunohistochemistry on colon cancer tissue microarrays to characterize the cell-type-specific distribution of CD82 and its associations with key markers of T cell dysfunction. CD82 expression was markedly increased in tumor-infiltrating immune and epithelial cells compared with normal tissues, particularly within exhausted CD8+ T cells. Elevated CD82 levels showed strong positive correlations with canonical exhaustion markers such as programmed cell death protein 1 and T cell immunoglobulin and mucin domain-containing protein 3. Multiplex immunohistochemical analysis further revealed that enrichment of CD82-positive epithelial regions and expansion of the CD82+TIM-3+PD-1+CD8+ T cell subset were associated with poor prognosis and were confirmed by multivariate Cox regression as independent risk factors for unfavorable survival. In patients who failed to achieve a complete pathological response following immunotherapy, exhausted CD8+ T cells exhibited significantly higher CD82 expression. Single-cell regulatory network analysis identified BATF and BHLHE40 as potential transcriptional regulators of CD82. Collectively, these findings demonstrate that CD82 promotes CD8+ T cell exhaustion, contributing to tumor progression and immunotherapy resistance in colon cancer. This study provides novel insight into the molecular mechanisms underlying immune dysfunction and offers a potential therapeutic target for reversing immunosuppression and improving immunotherapy efficacy in colon malignancies.

Keywords:  CD82; colon cancer; exhausted CD8+ T cells; multi-color immunohistochemistry; prognosis

DOI:  https://doi.org/10.3389/fimmu.2025.1731154
Proc Natl Acad Sci U S A. 2026 Feb 03. 123(5): e2532504123

Coordination of cell organelles to promote metabolon formation.

Zhou Sha, Anthony M Pedley, Timothy D Iles, Shaoqing Zhang, Jack R Staub, Ruobo Zhou, Stephen J Benkovic.

  The spatial coordination between cellular organelles and metabolic enzyme assemblies represents a fundamental mechanism for maintaining metabolic efficiency under stress. While previous work has shown that membrane-bound organelles regulate metabolic activities and that membrane-less condensates conduct metabolic reactions, the coordination between these two organizations remains unaddressed. By using a combination of proximity labeling, superresolution fluorescence microscopy, and metabolite analyses using isotopic tracing, we investigated the relationships between these metabolic hotspots. Here, we show that nutrient deficiency elongates mitochondria and transforms the ER from a tubular to sheet-like morphology, coinciding with increased mitochondrial respiration and inosine 5'-monophosphate levels. These structural changes promote the colocalization of purinosomes with these organelles, enhancing metabolic channeling. Disruption of ER sheet formation via MTM1 knockout destabilizes purinosomes, impairs substrate channeling, and reduces intracellular purine nucleotide pools without altering enzyme expression. Our findings reveal that organelle morphology and interorganelle contacts dynamically regulate the assembly and function of metabolic condensates, providing a structural basis for coordinated metabolic control in response to nutrient availability.

Keywords:  biomolecular condensates; cell metabolism; de novo purine biosynthesis; metabolon; purine

DOI:  https://doi.org/10.1073/pnas.2532504123
J Clin Invest. 2026 Jan 27. pii: e192928. [Epub ahead of print]

Targeting Pim2 Improves Antitumor Immunity through Promoting Effector Function and Persistence of CD8 T cells.

Yongxia Wu, Linlu Tian, Allison Pugel, Reza Alimohammadi, Qiao Cheng, Weiguo Cui, Michael I Nishimura, Lauren E Ball, Chien-Wei Lin, Shikhar Mehrotra, Andrew S Kraft, Xue-Zhong Yu.

  The PIM kinase family is critically involved in tumorigenesis, yet its role in primary T cells is understudied. We reported that PIM2, distinct from the other two isoforms, inhibits T-cell responses to alloantigen. Here, we further established PIM2 as a key negative regulator in anti-tumor immunity. Pim2 deficiency in tumor antigen-specific or polyclonal T cells enhanced their ability to control tumor growth in murine breast cancer, melanoma and leukemia models. Pim2 deficiency enhanced cytokine production and metabolic activities in tumor-infiltrating CD8 T cells. Pim2 deficiency increased TCF1 expression and memory-like phenotype in CD8 T cells from lymphoid organs. Mechanistically, PIM2 facilitated LC3 lipidation, P62 degradation and autophagic flux in T cells, leading to impaired glycolysis and effector cytokine production. Furthermore, through modulating VPRBP kinase phosphorylation, PIM2 inhibited histone methyltransferase activity of EZH2 in CD8 T cells, causing disrupted memory-like phenotype. Notably, the PIM2 inhibitor JP11646 markedly enhanced antitumor T-cell response. The immunosuppressive role of PIM2 was validated in human T cells, where inhibition of PIM2 enhanced antitumor responses in engineered human T cells including melanoma-specific TCR-T cells and CD19CAR-T cells. Collectively, PIM2 represents a promising target for improving cancer immunotherapy through enhancing effector differentiation and persistence of CD8 T cells.

Keywords:  Cell biology; Cellular immune response; Immunology; Immunotherapy; T cells

DOI:  https://doi.org/10.1172/JCI192928
Mol Ther. 2026 Jan 28. pii: S1525-0016(26)00029-8. [Epub ahead of print]

Enhancing Adoptive T Cell Therapy by Disrupting the SKI-SMAD2/3 Axis to Counteract TGF-β-Mediated Immunosuppression.

Xiaohan Jin, Jingxuan Yu, Xinyu Wu, Qingyong Hu, Xixi Chen, Wenbo Ma, Yude Guan, Dongmei Guo, Yulan Yang, Lingyu Wang, Guofei Jin, Zhenglan Han, Shumin Zhang, Nianchao Zhang.

Transforming growth factor beta (TGF-β) blockade broadly enhances antitumor immunity, while the in vivo mechanisms suppressing T cell-mediated tumor clearance remain elusive. Here, we uncover that TGF-β promotes T cell dysfunction by inducing degradation of the transcriptional co-repressor SKI, abolishing intrinsic repression of TGF-β signaling pathways. Notably, restoring SKI expression in chimeric antigen receptor (CAR)-T cells confers resistance to TGF-β-mediated immunosuppression. Proteomic analyses revealed that TGF-β stimulation triggers interaction between SMAD2/3 and SKI, leading to subsequent proteasomal degradation of SKI. Critically, engineering T cells to express SMAD2/3-binding-deficient SKI mutants (SKImut2/3) disrupts this interaction, preventing SKI degradation and significantly suppressing TGF-β signaling. Repeated tumor antigen stimulation assays under TGF-β pressure demonstrated that CAR-T cells transduced with SKImut2/3 exhibited heightened activation, increased cytokine production, and superior persistent cancer cell killing compared to unmodified cells or SKI-transduced cells in the presence of TGF-β1. Furthermore, transduction of SKImut2/3 in preclinical models of both T cell receptor (TCR) and CAR-T cell therapies prolonged survival in mice bearing xenografted liquid or solid tumors. Collectively, these findings establish SKImut2/3 expression as a promising therapeutic strategy to enhance both the durability and effector function of T cell-based cancer immunotherapies.

DOI: https://doi.org/10.1016/j.ymthe.2026.01.028
Front Oncol. 2025 ;15 1642022

Frontiers of cytokine engineering in CAR cell therapy for cancer.

Yinghan Wu, Yan-Ruide Li.

  Chimeric antigen receptor (CAR)-engineered T (CAR-T) cell therapy has revolutionized the treatment of hematologic malignancies, yet its efficacy in solid tumors remains limited by T cell exhaustion, restricted tumor infiltration, and an immunosuppressive tumor microenvironment (TME). Recent advances in cytokine engineering have introduced innovative strategies to overcome these barriers by modulating CAR cell survival, persistence, and cytotoxic function. This review provides a comprehensive analysis of emerging cytokine-augmented CAR platforms, highlighting mechanistic innovations such as IL-2 superkines that enhance selective CAR-T expansion, IL-15-armed CAR constructs that sustain in vivo persistence, and IL-12 and IL-18 co-expression systems that remodel the TME and recruit endogenous immune effectors. The roles of IL-7, IL-10, and IL-21 in preserving memory phenotypes, mitigating exhaustion, and improving metabolic fitness are also discussed in depth. Furthermore, the review explores synthetic and inducible cytokine circuits that enable spatial and temporal control of cytokine release, improving therapeutic precision and reducing systemic toxicity. Collectively, these innovations represent a paradigm shift toward next-generation, cytokine-engineered CAR therapies with enhanced efficacy, safety, and durability against both hematologic and solid tumors.

Keywords:  CAR-engineered T (CAR-T) cell therapy; antitumor capacity; cancer therapy; chimeric antigen receptor (CAR); cytokine; immunotherapy; in vivo persistence; invariant natural killer T (iNKT) cell

DOI:  https://doi.org/10.3389/fonc.2025.1642022
Biomedicines. 2026 Jan 11. pii: 152. [Epub ahead of print]14(1):

Loss of LXRβ Drives CD4+ T Cell Senescence and Exacerbates the Progression of Colitis.

Yang Zhang, Yalan Xu, Peng You, Yulan Liu, Jun Xu.

  Background: Liver X receptors (LXRs) are critical regulators of cholesterol homeostasis that modulate T cell function with anti-inflammatory effects. LXR downregulation has been implicated in the pathogenesis of inflammatory bowel disease (IBD), although its underlying mechanisms remain to be fully elucidated. Recent evidence has confirmed the link between T cell senescence and autoimmune diseases. Here, we sought to investigate whether and how LXRs regulate T cell senescence in controlling intestinal inflammation. Methods and Results: We found that LXRβ expression was decreased in the colons of mice with experimental colitis, and LXRβ deficiency (Lxrβ-/-) significantly aggravated their colitis. Intriguingly, this finding was accompanied by enhanced CD4+ T cell senescence both in the colons and spleens of Lxrβ-/- mice, evidenced by upregulation of SA-β-gal levels and the remarkable expansion of effector memory subclusters in CD4+ T cells. Moreover, senescent Lxrβ-/- CD4+ T cells secreted elevated levels of proinflammatory cytokines, especially in effector memory populations, exhibiting a pronounced proinflammatory phenotype. RNA-sequencing further confirmed the role of LXRβ in restricting CD4+ T cell senescence. Mechanistically, the absence of LXRβ in CD4+ T cells directly enhanced senescence by promoting the cGAS/STING pathway. Blocking STING signaling with a targeted inhibitor significantly alleviated senescence in Lxrβ-/- CD4+ T cells. Conclusions: Our findings demonstrate the role of LXRβ in regulating intestinal CD4+ T cell senescence to inhibit colitis development, identifying LXRβ as a potential therapeutic target for treating IBD.

Keywords:  LXRβ; T cell senescence; cGAS/STING pathway; colitis

DOI:  https://doi.org/10.3390/biomedicines14010152
Cancer Immunol Immunother. 2026 Jan 27. 75(2): 54

Empowering exhausted T cells of Glioblastoma patients by Neurotransmitters and Neuropeptides: decreasing immune checkpoint inhibitors, and increasing CD3zeta, proliferation and Glioblastoma arrest.

Mia Levite, Nili Ilouz, Eithan Galun, Yigal Shoshan.

   BACKGROUND: Glioblastoma is the most common malignant brain tumor, with extremely poor prognosis, and patient's T cells are exhausted, dysfunctional, and unable to eliminate Glioblastoma. To our knowledge, there is no effective and safe treatment for rejuvenating and improving multiple functions of exhausted T cells. We previously found that specific Neurotransmitters and Neuropeptides induce direct, potent and beneficial effects on human T cells.
METHOD: We studied if Dopamine, Glutamate, GnRH-II, Neuropeptide Y or their combinations, can rejuvenate and improve peripheral T cells of four Glioblastoma patients.
RESULTS: The Glioblastoma patients had abnormally low numbers of T cells, and mostly small T cells. Single Ex-vivo treatment (24 h) of Glioblastoma patient's T cells with either Dopamine, Glutamate, GnRH-II, or Neuropeptide Y, or their combinations (10-8 M, without any antigen/mitogen/cytokine/growth factor), induced multiple beneficial effects: 1. increased the number of live T cells; 2. decreased simultaneously all tested exhaustion-related immune checkpoint inhibitors: PD-1, Tim-3, LAG-3, TIGIT and CD160; 3. increased expression of TCR-associated CD3zeta; 4. increased proliferation of patient's T cells in response to human Glioblastoma cells; and 5. dramatically increased arrest of Glioblastoma cells by Glioblastoma patient's T cells.
CONCLUSIONS: Dopamine, Glutamate, Neuropeptide Y or GnRH-II, and the most beneficial being Dopamine + Neuropeptide Y, and Glutamate + Neuropeptide Y, can rejuvenate and improve Glioblastoma patient's T cells. They simultaneously decrease multiple immune checkpoint imhibitory receptors, and increase CD3zeta, T cell proliferation, and T cell anti-cancer activity. A novel 'Personalized Adoptive Neuro-Immunotherapy' was invented for Ex vivo rejuvenation and empowerment of patient's exhausted peripheral T cells by physiological Neurotransmitters/Neuropeptides, and their repeated infusion to patients.

Keywords:  CD160; Dopamine; Exhausted T cells; Glioblastoma; Glutamate; GnRH-II; Immunotherapy; LAG-3; Neuropeptide Y; Neuropeptides; Neurotransmitters; PD-1; T cells; TIGIT; Tim-3

DOI:  https://doi.org/10.1007/s00262-025-04226-6
Aging Cell. 2026 Feb;25(2): e70394

A Cellular and Transcriptomic Atlas of the Aged Mouse Hematopoietic System.

Ryan R White, Kun Xiong, Matthew Wakai, Allison Surian, Christina Adler, Nicole Negron, Min Ni, Tea Shavlakadze, Yu Bai, David J Glass.

Aging is a dominant risk factor for chronic diseases characterized by the functional decline of tissues and organs. During aging, the hematopoietic system declines in regenerative capacity-seemingly attributable to increases in DNA damage, replicative stress, and autophagic flux-resulting in skewing towards a myeloid lineage and away from a lymphoid lineage. Here, we characterized the transcriptomic and cellular landscape of the aged C57Bl/6J mouse hematopoietic system using a combination of bulk RNAseq and single cell RNAseq (scRNAseq). We show that aging leads to global transcriptional alterations in bulk peripheral blood mononuclear cells (PBMCs), lineage marker-depleted bone marrow cells (Lin-BM), and in hematopoietic stem and progenitor cells (HSPCs), immunophenotypically lineage marker negative (Lin-) Sca1+ cKit+ (LSK+). These changes indicate widespread activation of inflammatory processes, namely in PBMCs and Lin-BM cells. Interestingly, there is also a downregulation of cell cycle genes in HSPCs during aging. ScRNAseq across 39 hematopoietic cell types revealed age-related skewing in cell composition. Aged PBMCs showed significant decreases in CD4 and CD8 naïve cells concomitant with increases in CD4/8 memory and CD8 exhausted T cell populations. Lin-BM cells showed significant myeloid skewing in common myeloid progenitor (CMP) cells, as well as in the HSC population. We also identified a unique HSC population marked by increased Vwf, Wwtr1, and Clca3a1 expression that does not exist in young HSCs, thus likely marking true aged HSCs. Collectively, this work should serve as a useful resource for understanding and therapeutically targeting the aged hematopoietic system.

DOI: https://doi.org/10.1111/acel.70394
Cell Rep. 2026 Jan 22. pii: S2211-1247(25)01635-3. [Epub ahead of print]45(2): 116863

Activated CD38+ mast cells promote gastric cancer progression by suppressing CD8+ T cell cytotoxic activity through adenosine metabolism.

Jiabao Zhao, Deyi Feng, Fan Zhang, Shuntian Cai, Yubo Xiong, Guangchao Pan, Jingsong Ma, Jinshui Tan, Mengya Zhong, Zeyang Lin, Yifan Zhuang, Wei Wang, Huiwen Zhou, Shengyi Zhou, Ao Cheng, Meijuan Xu, Wenjie Ye, Hangzi Chen, Yongxi Song, Zhenning Wang, Xuehui Hong.

  Helicobacter pylori (H. pylori) infection is the primary driver in gastric cancer (GC) development, but the dynamic changes of the gastric mucosal microenvironment during H. pylori-associated GC progression remains elusive. Here, we perform single-cell RNA sequencing (scRNA-seq) on 21 gastric mucosae collected from four typical stages of GC progression under H. pylori infection. Our scRNA-seq analysis delineates the cellular landscape, dissects the dynamic alterations, and characterizes distinct immune cell populations. Notably, H. pylori-associated activated mast cells upregulate CD38 and COX2 expression, leading to increased secretion of adenosine and prostaglandin E2 (PGE2). PGE2 enhances adenosine receptor expression in CD8+ T cells, thereby suppressing their cytotoxicity via adenosine signaling. Cellular interactions are more complex at the GC stage than in the premalignant lesions. Collectively, our study offers a comprehensive insight into the evolving gastric mucosal microenvironment and validates the pro-tumor role of activated mast cells under H. pylori infection.

Keywords:  CP: cancer; CP: immunology; H. pylori; activated mast cell; gastric cancer

DOI:  https://doi.org/10.1016/j.celrep.2025.116863