bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–09–20
eight papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven
  1. ANKRD11 deficiency reprograms CD8+ T cell differentiation to enhance immunity in chronic infection and cancer.
  2. Spatial immune dysregulation in MASLD: integration of lobular zoning, metabolism and immune function.
  3. Neutrophil Senescence Induced by Tumor-Derived HMGB1 Promotes Hepatocellular Carcinoma Progression through Neutrophil Extracellular Trap-Mediated Suppression of CD8+ T Cell Immunity.
  4. Spatial ecotype in tumor immune exclusion: from spatial architecture to therapeutic strategies.
  5. DUSP4 promotes anti-tumor CD8+ T cell function and boosts CAR-T cell efficacy in mouse colorectal cancer.
  6. The spatial architecture of tumor immunity: Emerging predictive biomarkers across cancer.
  7. Epigenetic training licenses naïve CD8+ T cell metabolic fitness and function.
  8. Targeting PKM2 Enhances the Anti-Tumor Function of CD8+ T Cells Through Metabolic Reprogramming.
  1. Nat Immunol. 2026 Sep 11.
    ANKRD11 deficiency reprograms CD8+ T cell differentiation to enhance immunity in chronic infection and cancer.
    Wei Xu, Jie Guo, Xue Cao, Liping Li, Pei Xiao, Xinchao Zhang, Qiuzhu Jin, Fuping Zhang, Baidong Hou, Minghui Li, Xuyu Zhou.
      CD8+ T cell dysfunction is a major obstacle to hepatitis B virus (HBV) clearance and antitumor immunity. Here, using a humanized mouse model, we identify a T cell receptor targeting a clinically relevant HBV epitope and reveal ANKRD11 as a key epigenetic regulator of CD8+ T cell dysfunction in chronic infection and tumors. Ankrd11 knockout in CD8+ T cells enhances HBV-specific T cell proliferation and effector differentiation, especially under immunosuppressive conditions, via AP-1 family gene upregulation. Loss of Ankrd11 both drives the conversion of progenitor exhausted T cells into terminally exhausted T cells, and reprograms PD-1-TOX- tolerant cells into functional effectors, improving antiviral and antitumor responses. Ankrd11-deficient T cells show increased granzyme and superior effector function, enhancing viral control and tumor regression. These findings position ANKRD11 as a promising immunotherapy target for chronic HBV infection and cancer.
    DOI:  https://doi.org/10.1038/s41590-026-02652-x
  2. Front Immunol. 2026 ;17 1922207
    Spatial immune dysregulation in MASLD: integration of lobular zoning, metabolism and immune function.
    Dandan Gao, Xiaolei Wang, Shumin Mu, Yong Sun, Zhongming Wu.
      Most prior studies on immune-related fatty liver disease have focused on changes in immune cell quantity and composition. However, this "cell-count model" does not fully explain the regional onset of fibrosis, spatial heterogeneity of lesions, or variable immunotherapy responses. Immune dysregulation in metabolic dysfunction-associated steatotic liver disease (MASLD) involves not only compositional changes but also spatial redistribution and functional alterations of immune cells within specific hepatic lobule regions. Emerging multi-omics and spatial transcriptomic data suggest that chemokine gradient remodeling, metabolic microenvironment reprogramming, and circadian rhythm disruption may drive immune cell relocation along the portal-central axis. We propose that immune dysregulation in MASLD reflects a disruption of spatial immune homeostasis and introduce the liver lobule as the basic unit for spatial immune analysis. The lobule comprises three functionally distinct zones: the periportal zone (zone 1), which serves as the primary immune surveillance barrier; the pericentral zone (zone 3), characterized by metabolic stress and functional impairment; and the fibrotic septum, which in advanced disease creates a structurally confined immunosuppressive niche. To quantify regional T cell dysfunction, we propose a Regional Exhaustion Index (REI) as a conceptual framework, calculated as the ratio of PD-1+TIM-3+ CD8+ T cells to total CD8+ T cells within a defined microanatomical region. This metric translates regional immune conditions into a quantifiable measure of T cell functional impairment across different lobular zones. We outline how chemokine remodeling, metabolic reprogramming, and circadian disruption drive spatially distinct immune alterations: reduced immune surveillance in zone 1, functional impairment in zone 3, and structural confinement in the fibrotic septum. We also discuss the translational potential of this framework for biomarker discovery, patient stratification, and targeted therapy. The REI remains an exploratory metric requiring validation of its biological meaning and clinical utility. Current evidence is largely correlational, and the causal role of spatial immune changes in disease progression demands further investigation. Nonetheless, this spatial perspective complements existing paradigms and may guide the development of spatially targeted therapeutic strategies.
    Keywords:  immune exhaustion; liver lobule partitioning; macrophage heterogeneity; metabolic dysfunction-associated steatotic liver disease; regional exhaustion index; spatial immunology
    DOI:  https://doi.org/10.3389/fimmu.2026.1922207
  3. Cancer Commun (Lond). 2026 ;46 0050
    Neutrophil Senescence Induced by Tumor-Derived HMGB1 Promotes Hepatocellular Carcinoma Progression through Neutrophil Extracellular Trap-Mediated Suppression of CD8+ T Cell Immunity.
    Yaqian Duan, Shan Yu, Xuanyi Wang, Rong Wu, Yuqing Zhao, Xuehua Kong, Shiyu Cao, Dan Xiang, Rui Wu, Jingying Zhou, Yang Luo, Liang Duan.
      Background: Immune cells are essential components of the tumor microenvironment. Among them, neutrophils have gained increasing interest due to their marked heterogeneity. This study focused on aged neutrophils, aiming to uncover their mechanistic contribution to hepatocellular carcinoma (HCC) progression and evaluate their potential clinical importance. Methods: This study included analyses of 2 public datasets (GSE149614 and GSE189903) as well as a clinical cohort comprising 105 patients with HCC and 41 healthy controls. The abundance of aged neutrophils and CD8+ T cells as well as their clinical correlation were assessed, and their potential clinical value was explored. In vitro cellular experiments were used to dissect the molecular mechanisms responsible for CD8+ T cell suppression by aged neutrophils and the progression of neutrophil senescence. In addition, a variety of in vitro and in vivo experiments were performed to evaluate the involvement of aged neutrophils in HCC progression. Results: Peripheral blood and tumor tissues from HCC patients exhibited a marked accumulation of aged neutrophils, which was inversely correlated with CD8+ T cell abundance. Aged neutrophils released excessive neutrophil extracellular traps (NETs) via a caspase-3-dependent mechanism, thereby impairing CD8+ T cell proliferation and activation. Functionally, this suppression of CD8+ T cell activity promoted malignant behaviors of HCC cells, including enhanced proliferation, reduced apoptosis, and increased angiogenesis. In vivo, accumulation of aged neutrophils accelerated HCC progression through CD8+ T cell dysfunction, with minimal impact on distant metastasis. Mechanistically, HCC cell-derived high-mobility group box 1 (HMGB1) induced neutrophil senescence via activation of the Toll-like receptor 4 (TLR4) signaling pathway. Clinically, integrating circulating aged neutrophil with α-fetoprotein (AFP) substantially improved early HCC detection, while the CD8+ T cell-to-aged neutrophil ratio demonstrated strong potential for malignant risk stratification. Conclusion: These findings identify HCC cell-derived HMGB1 as a driver of neutrophil senescence and reveal that aged neutrophils promote HCC progression by inducing CD8+ T cell dysfunction through NET release. More importantly, aged neutrophils represent a robust noninvasive candidate marker for both HCC detection and assessment of malignant risk.
    DOI:  https://doi.org/10.34133/cancomm.0050
  4. Mol Cancer. 2026 Aug 14. pii: 217. [Epub ahead of print]25(1):
    Spatial ecotype in tumor immune exclusion: from spatial architecture to therapeutic strategies.
    Ming Ying, Lei Zhang, Mengwei Jia, Xiaofei Sun, Yibo Su, Chengcheng Liu, Ming Gong, Tao Sun, Bin Zhang.
      The tumor microenvironment (TME) exhibits widespread immunophenotypic heterogeneity. Based on the spatial immune contexture, tumor immune profiles can be classified as immune-inflamed, excluded, or desert. Immune-excluded tumors, a distinct tumor immune phenotype, are characterized by the presence of immune cells (especially CD8+ T cells) near tumors but a lack of direct physical contact between immune and tumor cells. Accumulating evidence indicates that tumor immune exclusion is a spatially organized and actively maintained microenvironmental state associated with poor prognosis, impaired T cell infiltration, and resistance to immunotherapy. However, the biological mechanisms and spatial profiling underlying this phenotype remain unclear. Advances in spatial omics technologies and analytical tools have enabled the dissection of the complex spatial architecture of immune-excluded tumors. In this review, we describe recent insights into the core cellular subsets and spatial interaction networks of immune-excluded tumors, incorporating the spatial immune contexture, to provide new theoretical foundations and intervention strategies targeting spatial ecotypes to enhance T cell infiltration and sensitize immune-excluded tumors to immunotherapy. Collectively, these findings support a shift from cell-centric models towards ecotype-centered frameworks in which spatially coordinated cellular alliances govern immune accessibility and therapeutic response. Furthermore, we discuss current challenges in this field, including standardization of spatial multi-omics data integration, real-time monitoring of dynamic spatiotemporal evolution, and optimization of clinical translation pathways. Future investigations should incorporate long-term sampling, organoid models, and basket trial designs to enable precise immune-intervention strategies based on spatial ecotypes.
    Keywords:  Immune exclusion; Immunotherapy resistance; Spatial ecotype; Spatial omics; Tumor microenvironment
    DOI:  https://doi.org/10.1186/s12943-026-02766-8
  5. Nat Commun. 2026 Aug 15. pii: 9811. [Epub ahead of print]17(1):
    DUSP4 promotes anti-tumor CD8+ T cell function and boosts CAR-T cell efficacy in mouse colorectal cancer.
    Heng Li, Clara K T Koh, Tianshuai Zhang, Yi Lu, Chin Wen Png, Dong Van Hoang, Min Hui Oon, Choon Seng Chong, Kai Zhuang, Guanyu Yu, Jie Wan, Ker-Kan Tan, Huanhuan Luo, Jun Siong Low, Wei Zhang, Nicholas R J Gascoigne, Yongliang Zhang.
      The activation and function of CD8+ T cells, which are central for anti-tumor immunity, are tightly regulated by extracellular and intracellular signaling pathways. Dual-specificity phosphatases (DUSP), including DUSP4, dephosphorylate serine/threonine and tyrosine residues of proteins to modulate cellular signaling. Here, we investigate the role of DUSP4 in cancer immunity. Patients with colorectal cancers (CRC) with lower DUSP4 expression across the CRC tissue exhibit shorter survival compared to those with higher DUSP4 expression. By contrast, in AOM/DSS-induced male mouse CRC models, global DUSP4 deficiency enhances tumorigenesis and compromises CD8+ T cell-mediated anti-tumor immunity. Mechanistically, DUSP4 knockout increases ERK2-mediated expression of the T cell activation regulator Klf2, thereby suppressing KLF2-mediated cytotoxic programs. In a CD19+ CRC xenograft mouse model, CRISPRa-mediated DUSP4 activation promotes anti-CD19 CAR-T cell proliferation and anti-tumor cytotoxicity. Thus, our data show that DUSP4 supports CD8+ T cell cytotoxic functions and suggest that DUSP4 may be a promising therapeutic target for enhancing anti-tumor immunity.
    DOI:  https://doi.org/10.1038/s41467-026-76779-8
  6. Immunol Res. 2026 Sep 12. pii: 110. [Epub ahead of print]74(1):
    The spatial architecture of tumor immunity: Emerging predictive biomarkers across cancer.
    Xiaoying Li, Ruizhen Li, Huanhuan Wang, Pei Zhang, Dan Cao, Fan Zhang.
      Tumor immunity is shaped not only by the cellular composition of the tumor microenvironment (TME), but also by its spatial architecture. Increasing evidence shows that immune function cannot be inferred from cell abundance alone, because the positioning and coordination of immune and stromal cells determine whether local immunity is activated, excluded, or suppressed. Advances in multiplex imaging, spatial proteomics, spatial transcriptomics, and AI-assisted tissue analysis now enable high-resolution mapping of these spatial states across clinically relevant scales. These approaches reveal that tumors are organized as recurrent microarchitectures that can function either as immune engines or as suppressive brakes. Immune-supportive structures, including mature tertiary lymphoid structures, dendritic cell-centered immune triads, high endothelial venule-associated recruitment corridors, and effector-tumor interfaces, promote antigen presentation, lymphocyte recruitment, and cytotoxic engagement. In contrast, exclusionary and suppressive architectures, such as CAF-mediated stromal barriers, SPP1 + macrophage-CAF niches, stalled T-cell zones, Treg-enriched suppressive niches, and NLRP3 + macrophage-rich regions, restrict infiltration and sustain immune dysfunction. Across cancer types, such spatial readouts are emerging as robust biomarkers. In this Review, we summarize recent progress in spatial tumor immunology and propose a conceptual framework for interpreting tumor immunity from composition to cellular neighborhoods. We further discuss how these spatial architectures shape tumor heterogeneity, therapeutic response, and resistance, and how they may be translated into actionable biomarkers for patient stratification, treatment monitoring, and next-generation precision immunotherapy.
    Keywords:  Immune exclusion; Predictive biomarkers; Spatial biology; Tertiary lymphoid structures; Tumor microenvironment
    DOI:  https://doi.org/10.1007/s12026-026-09844-5
  7. Sci Adv. 2026 Sep 18. 12(38): eaee8251
    Epigenetic training licenses naïve CD8+ T cell metabolic fitness and function.
    Mengjie Lv, Jiyu Ding, Haizhen Long, Qian Chai, Lili Xu, Caiwei Jin, Wei Liang, Liwei Zhang, Bangmin Zhang, Zhihan Lv, Jicheng Zhao, Guohong Li, Mingzhao Zhu.
      Naïve T cells maintain quiescence yet must respond rapidly to antigens, but how they prime this capacity is unclear. We identify histone variant H2A.Z as a key regulator of an epigenetic training program that licenses quiescent naïve CD8+ T cells for future activation. H2A.Z deficiency disrupts naïve T cell homeostasis and effector responses. Multiomics reveals that H2A.Z is selectively deposited at oxidative phosphorylation (OXPHOS) gene promoters in quiescent naïve CD8+ T cells, priming the chromatin for rapid transcriptional induction. This training is developmentally instructed by tonic interleukin-7 (IL-7) signaling and regulated by transcription factor GABPα. Age-related decline in IL-7 signaling reduces H2A.Z occupancy and impairs T cell activation, while IL-7 supplementation or enforced H2A.Z expression rescues this defect. H2A.Z overexpression also enhances chimeric antigen receptor T cell stemness and antitumor efficacy. Our work defines an IL-7R-GABPα-H2A.Z-OXPHOS axis that epigenetically establishes metabolic and functional fitness in quiescent T cells, offering insights for immunotherapy targeting ageing and tumors.
    DOI:  https://doi.org/10.1126/sciadv.aee8251
  8. Int J Mol Sci. 2026 Aug 27. pii: 7664. [Epub ahead of print]27(17):
    Targeting PKM2 Enhances the Anti-Tumor Function of CD8+ T Cells Through Metabolic Reprogramming.
    Junxiu Zhang, Shuyi Wu, Qin Yin, Yanglin Liu, Shuguo Zheng, Peiwei Yang.
      The efficacy of adoptive cell transfer (ACT) therapy in solid tumors is often limited by the functional exhaustion and insufficient persistence of infused CD8+ T cells within the tumor microenvironment. Through the integrated analysis of single-cell transcriptomic data, this study identified enolase 1 (ENO1), a key rate-limiting enzyme in glycolysis, as a core gene highly correlated with the superior anti-tumor phenotype of tumor-infiltrating lymphocytes (TILs). However, in vitro functional validation demonstrated that the overexpression of Eno1 failed to substantially enhance the anti-tumor efficacy of mouse T cells, suggesting the presence of a downstream metabolic regulatory node within the glycolytic cascade that restricts the conversion of carbon flux. To overcome this limitation, we introduced the small molecule activator TEPP-46 to target a crucial downstream metabolic hub, pyruvate kinase M2 (PKM2). Transcriptome sequencing confirmed that PKM2 activation successfully induced systemic metabolic rewiring in CD8+ T cells and broadly upregulated the expression of cytotoxicity- and memory-related genes. In an in vivo B16-OVA melanoma model, OT-1 T cells subjected to In vitro TEPP-46 pretreatment exhibited significantly enhanced tumor-suppressive capabilities and effectively promoted the preferential differentiation of T cells into central memory T cells (Tcm). In summary, this study highlights the importance of targeting downstream metabolic nodes to bypass intrinsic metabolic restrictions in T cells. It demonstrates that in vitro metabolic pretreatment via PKM2 activation represents an effective translational strategy for optimizing the anti-tumor efficacy of ACT cell products.
    Keywords:  CD8+ T cells; adoptive cell transfer; enolase 1; glycolysis; metabolic reprogramming
    DOI:  https://doi.org/10.3390/ijms27177664
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