bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–08–09
seven papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven
  1. Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.
  2. T cell-based immunotherapy in solid tumors: mechanistic barriers and emerging opportunities.
  3. Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.
  4. Tumoral AMER1 driven dopamine synthesis triggers cancer cell pyroptosis and licenses CD8+ T cell immunity in colorectal cancer.
  5. Metabolic rewiring of the dendritic cell-T cell axis: tumour-derived barriers and therapeutic opportunities.
  6. Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance.
  7. Spatiotemporal dynamics of the tumor microenvironment in hepatocellular carcinoma during combination immunotherapy.
  1. Signal Transduct Target Ther. 2026 Aug 07. pii: 314. [Epub ahead of print]11(1):
    Post-translational modifications in metabolic reprogramming: implications for metabolic therapy and immunotherapy in cancer.
    Si-Jie Chen, Shi-Wei Yue, Yun-Pu Zhang, Hui-Fang Liang, Hai-Xin Wu, Xiao-Ping Chen, Bi-Xiang Zhang, Wei Zhang.
      Cancer metabolism is characterized by profound reprogramming, yet the mechanisms enabling rapid and precise adaptation remain incompletely understood. This review establishes post-translational modifications (PTMs) as the central processing unit of oncogenic metabolic reprogramming. PTMs execute a conserved three-tiered regulatory logic: they interpret oncogenic and environmental signals, command metabolic flux, and cement malignant phenotypes through epigenetic and feedback mechanisms. We systematically demonstrate how this PTM-driven logic governs key pillars of cancer metabolism-glucose, lipid, amino acid, and nucleotide utilization-and extends its command to critical cell fate execution programs, including mitochondrial dynamics, autophagy, and ferroptosis. Furthermore, we delineate how PTMs act as master regulators of immunometabolic reprogramming within the tumor microenvironment (TME), directly linking tumor metabolism to T cell exhaustion, myeloid cell polarization, and immune evasion. By integrating recent advances on the determinants and crosstalk of PTM networks, we describe how metabolic plasticity and heterogeneity are encoded at the PTM level, with metabolic gradients shaping distinct "PTM geographies" within tumors. Finally, we translate these insights into clinical prospects, highlighting PTM-based biomarkers, PTM-targeted drugs and emerging therapeutic strategies, including targeted protein degradation, PTM-targeted vaccines and dietary interventions. Deciphering this PTM-encoded program reveals a new landscape of therapeutic vulnerabilities, shifting the paradigm toward rationally targeting the fundamental computational logic that sustains tumors.
    DOI:  https://doi.org/10.1038/s41392-026-02862-7
  2. BMB Rep. 2026 Aug 03. pii: 6874. [Epub ahead of print]
    T cell-based immunotherapy in solid tumors: mechanistic barriers and emerging opportunities.
    Hojin Chun, Hyunjin Ju, Sung-Min Hwang.
      T cell-based immunotherapies have transformed the treatment of hematological malignancies, but their efficacy in solid tumors remains inconsistent. Unlike blood cancers, solid tumors present multiple barriers that impede T cell infiltration, metabolic fitness, antigen recognition, and long-term persistence. These barriers include structural exclusion by the stroma, tumor-driven metabolic competition, antigen plasticity, and the progressive epigenetic fixation of T cell exhaustion states. This review integrates our current understanding of T celldirected therapeutic approaches and examines the tumorintrinsic and microenvironmental mechanisms that limit their activity in solid malignancies. We discuss how chronic stress signaling, altered nutrient availability, glycan-mediated epitope masking, and transcriptional reprogramming collectively destabilize therapeutic T cell function. Finally, we evaluate emerging strategies designed to remodel the tumor niche, diversify antigen targeting, and enhance T cell metabolic and epigenetic resilience. Thus, developing a mechanistic framework that combines intrinsic T cell reprogramming with adaptation to the tumor context will be crucial for extending durable T cell-mediated immunity to solid cancers.
  3. Front Cell Dev Biol. 2026 ;14 1885974
    Glucose metabolism in tumor-associated macrophage plasticity and cancer immunity.
    Bang Liu, Jin Wang, Xiulin Jiang, Xiangyu Chen.
      Tumor-associated macrophages (TAMs) are key immune cells in the tumor microenvironment and play critical roles in tumor progression, immune escape, and therapeutic response. Their functional plasticity is closely regulated by metabolic reprogramming, particularly glucose metabolism. Glucose-related pathways, including glycolysis, gluconeogenesis, the pentose phosphate pathway, glycogen metabolism, and pyruvate/lactate metabolism, influence TAM polarization, cytokine production, phagocytosis, antigen presentation, and T cell interactions. In many tumors, enhanced glycolysis and lactate accumulation promote M2-like TAM polarization and suppress CD8+ T cell activity, whereas certain metabolic programs may support M1-like anti-tumor functions under specific conditions. This mini review summarizes major glucose metabolic pathways involved in TAM regulation, highlights their context-dependent pro- and anti-tumor roles, and discusses therapeutic strategies for reprogramming TAM metabolism to improve anti-tumor immunity and immunotherapy response.
    Keywords:  HIF-1α; glucose metabolism; glycolysis; immunometabolism; lactate; metabolic reprogramming; pentose phosphate pathway (PPP); pyruvate metabolism
    DOI:  https://doi.org/10.3389/fcell.2026.1885974
  4. Cancer Lett. 2026 Aug 03. pii: S0304-3835(26)00536-7. [Epub ahead of print]659 218772
    Tumoral AMER1 driven dopamine synthesis triggers cancer cell pyroptosis and licenses CD8+ T cell immunity in colorectal cancer.
    Jun Long Dang, Qi Hu, Yang Lu, Jie Wang, Xiaoxue Li, Yixiong Chen, Jun Zhao, Yu Liu, Julie Wang, Nianke Zang, Li Zhou, Xiaolan Zhong, Wanglin Li, Song Guo Zheng.
      While classical tumor suppressors in colorectal cancer (CRC) are predominantly recognized for restraining cell-autonomous proliferation, their extrinsic mandate in orchestrating the tumor immunometabolic niche remains poorly defined. Clinically, we document that APC membrane recruitment protein 1 (AMER1) downregulation correlates with advanced progression and cytotoxic CD8+ T cell spatial exclusion in CRC patients. Using parallel homograft models in diverse host immune backgrounds, we show that tumoral AMER1 confers robust in vivo tumor-suppressive effects that are dependent on a fully functional immune system. Single-cell RNA sequencing reveals that tumoral AMER1 enrichment actively preserves CD8+ T cell effector stemness by expanding the CXCR5+ precursor exhausted subset (Tpex) across regional lymph nodes and primary tumor microenvironments. Integrated multi-omics and biochemical tracking identify dopamine (DA) as the conserved neurometabolic effector driving this niche remodeling. Mechanistically, AMER1 physically binds and rescues dopa decarboxylase (DDC) from post-translational degradation to sustain tumoral DA secretion; conversely, AMER1 loss creates a localized DA void. Cell-autonomously, tumoral DA accumulation triggers gasdermin D (GSDMD)-dependent tumor pyroptosis. Therapeutically, local DA administration halts multi-lineage carcinoma progression by reversing CD8+ T cell terminal exhaustion and reinforcing central memory differentiation. Collectively, our findings redefine AMER1 as a critical immunometabolic gatekeeper and establish neurotransmitter metabolic bypassing as a promising therapeutic strategy for CRC.
    Keywords:  AMER1/WTX; CD8(+) T cell stemness; Colorectal cancer; Dopamine decarboxylase; Neuro-immunometabolism; Tumor pyroptosis
    DOI:  https://doi.org/10.1016/j.canlet.2026.218772
  5. Exp Mol Med. 2026 Aug 06.
    Metabolic rewiring of the dendritic cell-T cell axis: tumour-derived barriers and therapeutic opportunities.
    Minkyu Cho, Minkyung Song.
      The tumour microenvironment imposes severe metabolic constraints that reshape anti-tumour immunity across the cancer-immunity cycle. Rather than serving merely as passive byproducts of tumour growth, tumour-derived metabolites and nutrient imbalances act as potent metabolic checkpoints-stage-specific barriers that disrupt the functional progression of dendritic cells (DCs) and T cells from antigen presentation to effective tumour clearance. In this review, we propose a framework that overlays the cancer-immunity cycle with major metabolic checkpoints, including glucose and amino acid competition, acidosis and lipid overload, to clarify how distinct metabolic stresses create immune bottlenecks at different stages of the anti-tumour response. We then discuss how distinct tumour metabolic phenotypes, characterized by high glycolysis, amino acid dependency or lipid dysregulation, generate local environmental stresses that differentially reprogram DC function and T cell fitness. Particular emphasis is placed on the DC-T cell axis as a critical site where multiple metabolic defects converge, destabilizing antigen presentation, co-stimulation and immunological synapse function. We further survey emerging therapeutic strategies aimed at restoring the DC-T cell axis and effective anti-tumour immunity, ranging from small-molecule metabolic inhibitors to metabolically engineered adoptive cell therapies designed to function in hostile microenvironments. Finally, we highlight emerging technologies such as single-cell and spatial multi-omics, real-time metabolic imaging and microphysiological systems that can resolve the spatiotemporal heterogeneity of tumour immunometabolism and support more precise immunometabolic interventions.
    DOI:  https://doi.org/10.1038/s12276-026-01798-w
  6. Front Immunol. 2026 ;17 1894658
    Metabolic immune checkpoints in cancer: how tumor-derived metabolites shape immunotherapy resistance.
    Renjie Pan, Dongdong Chen, Yilu Wu, Lancheng Zhang, Jing Zhang, Junjie Li, Qiuxia Zhao, Yan Tang.
      Immune checkpoint blockade has transformed cancer therapy, yet many tumors remain intrinsically resistant or acquire resistance after initial response. Increasing evidence indicates that this failure is not determined solely by PD-1, PD-L1, CTLA-4, or T-cell exhaustion, but also by metabolically suppressive states within the tumor microenvironment. Tumor-derived metabolites can function as metabolic immune checkpoints by limiting effector immune activity, promoting regulatory or myeloid suppressive compartments, and weakening immunotherapy efficacy. This mini review summarizes recent experimental evidence showing how lactate, adenosine, tryptophan-derived metabolites, and nucleotide-derived metabolites shape immune escape and resistance to immune checkpoint blockade. Lactate links tumor glycolysis to Treg recruitment, impaired T-cell function, and lactylation-associated therapeutic resistance. The CD73-adenosine axis suppresses CD8+ T cells and natural killer cells while reinforcing regulatory and myeloid immune programs. Tryptophan-derived metabolites extend beyond the classical IDO1-kynurenine-AhR pathway to involve non-classical checkpoints such as Siglec-15 and broader kynurenine/indole/serotonin networks. Emerging evidence further identifies nucleotide-derived UDP signaling as a driver of macrophage-mediated immunosuppression. Finally, we discuss how targeting metabolic checkpoints in combination with immune checkpoint blockade may improve therapeutic responses. Defining the spatial and cellular contexts of metabolite-mediated immune suppression may enable more precise strategies to overcome immunotherapy resistance.
    Keywords:  adenosine; immunotherapy resistance; lactate; metabolic immune checkpoint; tryptophan metabolism; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1894658
  7. Hepatol Commun. 2026 Sep 01. pii: e1014. [Epub ahead of print]10(9):
    Spatiotemporal dynamics of the tumor microenvironment in hepatocellular carcinoma during combination immunotherapy.
    Hitoshi Iwasaki, Shinji Itoh, Katsuya Toshida, Junya Mita, Takuma Ishikawa, Norifumi Iseda, Kyohei Yugawa, Shohei Yoshiya, Takashi Motomura, Takeo Toshima, Shinichi Aishima, Yoshinao Oda, Tomoharu Yoshizumi.
       BACKGROUND: Atezolizumab plus bevacizumab (ATZ/BEV) is a standard first-line therapy for advanced hepatocellular carcinoma (HCC); however, many patients do not achieve meaningful tumor regression. The temporal and spatial immune remodeling associated with ATZ/BEV remains poorly understood.
    METHODS: We performed single-cell RNA sequencing of paired hepatectomy specimens obtained before and after ATZ/BEV from one patient and of tumor center and margin samples from another patient after ATZ/BEV. Cell composition, subclusters, and cell-cell communication were analyzed. In addition, candidate molecules identified by transcriptomic analysis were further assessed using serum-based assays and immunohistochemistry.
    RESULTS: These single-cell analyses suggested that ATZ/BEV was associated with a shift toward an immune-active tumor microenvironment, with increased CD8+ T cells together with reduced endothelial cells. CD8+ T cells showed increased effector and exhaustion signatures, indicating coexistence of activation and dysfunction. CellChat analysis demonstrated selective activation of the TIGIT-PVR/NECTIN2 axis after treatment. Spatial analysis showed that the tumor margin was enriched for CD8+ T cells and exhibited stronger effector and exhaustion activity than the tumor center. Immunoregulatory signaling was also more prominent at the margin. Serum TIGIT levels were significantly higher after ATZ/BEV than in upfront resection cases (p=0.0325). Immunohistochemistry showed greater margin-to-center differences in TIGIT (p=0.0019) and PVR (p=0.0008) in the tumor after ATZ/BEV.
    CONCLUSIONS: Our exploratory findings suggest that ATZ/BEV may remodel the HCC microenvironment toward a state characterized by concurrent CD8+ T-cell activation and inhibitory signaling through the TIGIT-PVR/NECTIN2 axis, particularly at the tumor margin.
    Keywords:  TIGIT; atezolizumab; bevacizumab; poliovirus receptor; single-cell gene expression analysis
    DOI:  https://doi.org/10.1097/HC9.0000000000001014
This page is being maintained by Thomas Krichel. It was last updated on 2026‒08‒09 at 6:54.