bims-spamet Biomed News
on Spatial metabolomics of T cells
Issue of 2026–10–11
nine papers selected by
Peio Azcoaga, Katholieke Universiteit te Leuven
  1. Protocol for analyzing tumor-infiltrating bystander CD8+ T cells in mice using adoptive transfer of P14 TCR-transgenic CD8+ T cells.
  2. Spatial Proximity Mapping Identifies Vulnerabilities for Therapeutic Co-Targeting.
  3. Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
  4. Extracellular matrix-targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors.
  5. Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.
  6. Advances in IL-2-based cancer immunotherapy and the synergistic role of stem-like CD8+ T cells in IL-2 and PD-1 combination therapy.
  7. Spatial proteomics: technical evolution and applications in cancer research.
  8. PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.
  9. Metabolite-driven dysfunction of intratumoral tertiary lymphoid structures: single-cell and spatial omics perspectives on cancer immune escape.
  1. STAR Protoc. 2026 Oct 06. pii: S2666-1667(26)00539-3. [Epub ahead of print]7(4): 104886
    Protocol for analyzing tumor-infiltrating bystander CD8+ T cells in mice using adoptive transfer of P14 TCR-transgenic CD8+ T cells.
    Chunyang Xie, Wenwen Xi, Hairu Wang, Lilin Ye, Xiangyu Chen, Yao Lin.
      While tumor-specific CD8+ T cells become functionally exhausted within the tumor microenvironment (TME), virus-specific bystander memory CD8+ T (TBYS) cells are abundant and represent valuable immunotherapy targets. Here, we present a protocol to analyze tumor-infiltrating virus-specific TBYS cells in murine tumor models using P14 CD8+ T cells. We describe steps for monitoring long-term in vivo behavior of P14 TBYS cells and characterizing their differentiation trajectories and functional heterogeneity. For complete details on the use and execution of this protocol, please refer to Lin et al.1.
    Keywords:  Cancer; Cell isolation; Flow Cytometry; Immunology; Model Organisms
    DOI:  https://doi.org/10.1016/j.xpro.2026.104886
  2. Cancer Discov. 2026 Oct 08. OF1
    Spatial Proximity Mapping Identifies Vulnerabilities for Therapeutic Co-Targeting.
      
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2026-090
  3. Cell. 2026 Oct 06. pii: S0092-8674(26)01122-0. [Epub ahead of print]
    Cancer competition for vitamin B2 creates metabolic checkpoint for T cell ferroptosis.
    Huanpeng Chen, Chao Li, Yujing Ke, Zilong Wu, Ziwei Ou, Nanqi Huang, Zhenyu Lin, Huixin Gao, Xuehu Xu, Lijuan Lu, Zhaofeng Huang, Yingjie Bian.
      Metabolic competition between tumors and T cells drives immune evasion, but the transporters and mechanisms remain largely elusive. Here, we establish the CareSLCs platform and identify that SLC52A3-mediated vitamin B2 (VB2) uptake is indispensable for T cell antitumor immunity. Mechanistically, VB2 deficiency impairs mitochondrial respiration and glutathione regeneration, leading to mitophagy, labile iron accumulation, and lipid peroxidation that trigger T cell ferroptosis. Unexpectedly, tumors preferentially employ SLC52A2, not SLC52A3, to scavenge VB2 and outcompete T cells. Tumor SLC52A2 ablation enhances T cell function in immunocompetent hosts without appreciably affecting intrinsic tumor growth. Clinically, high tumoral SLC52A2 correlates with T cell dysfunction and poor survival, whereas dietary VB2 intake is associated with reduced cancer risks. Thus, VB2 supplementation or SLC52A3 overexpression augments CAR-T cell antitumor efficacy. Our results suggest that tumoral VB2 competition establishes a metabolic checkpoint driving T cell ferroptosis and that enhancing VB2 uptake reinvigorates T cells to improve cancer immunotherapy.
    Keywords:  CAR-T cell therapy; SLC52A2; SLC52A3; ferroptosis; metabolic competition; vitamin B2
    DOI:  https://doi.org/10.1016/j.cell.2026.09.020
  4. Sci Adv. 2026 Oct 09. 12(41): eaeh3957
    Extracellular matrix-targeted TNC-scFv armoring enhances CAR T cell persistence and antitumor activity in solid tumors.
    Kaizhao Chen, Qi Fu, Wei Zhang, Ziyang Lin, Longjun Chen, Youxi Zhou, Yongkun Huo, Ziqing Gao, Haoyang Wan, Caifang Wang, Xingxu Huang, Shuaishuai Zhang, Ming Liu, Xiaodong Ma.
      Chimeric antigen receptor T cell (CAR T cell) therapy has shown limited efficacy in solid tumors, largely due to physical and immunosuppressive barriers imposed by the tumor microenvironment (TME). Tenascin-C (TNC), an extracellular matrix protein highly expressed in multiple solid malignancies, contributes to immune exclusion and T cell dysfunction. Here, we engineer an armored CAR T cell platform that locally targets the extracellular matrix by secreting a TNC-specific single-chain variable fragment (TNC-scFv) linked to conventional CAR architecture. TNC-scFv-armored CAR T cells exhibit enhanced cytotoxic activity, improved persistence, and reduced exhaustion in vitro and in xenograft tumor models. Single-cell transcriptomic analysis reveals that TNC targeting reprograms the TME toward a CD8+ T cell-enriched and functionally active immune landscape. In humanized tumor models, TNC-scFv-armored CAR T cells mediate robust antitumor responses with minimal systemic toxicity. This extracellular matrix-targeted armoring framework is compatible with additional immunomodulatory payloads, as illustrated by combinatorial armoring with interleukin-2, which further enhances efficacy while mitigating cytokine-associated toxicity. Together, these results establish extracellular matrix-directed armoring as a generalizable strategy to improve CAR T cell therapy for solid tumors.
    DOI:  https://doi.org/10.1126/sciadv.aeh3957
  5. Front Immunol. 2026 ;17 1908222
    Mitochondrial dysfunction as a metabolic checkpoint of immunotherapy response in colorectal cancer.
    Lorenzo Tomassini, Marco Colella, Giovanni Monteleone, Carmine Stolfi, Federica Laudisi.
      Immunotherapy has markedly improved outcomes across multiple cancer types; however, colorectal cancer (CRC) remains largely refractory, with meaningful responses mostly restricted to tumors harboring deficient mismatch repair and high microsatellite instability (dMMR/MSI-H), which represent only a small fraction of CRC cases. Emerging evidence suggests that mitochondrial dysfunction may be viewed as a metabolic checkpoint, representing a conceptual framework through which mitochondrial-dependent processes regulate antitumor immunity and immunotherapy response in CRC. In tumor cells, mitochondrial reprogramming enhances reliance on oxidative phosphorylation, promotes hypoxia, and drives metabolite accumulation, collectively shaping an immunosuppressive tumor microenvironment. In parallel, tumor-infiltrating T-cells exhibit mitochondrial dysfunction characterized by impaired biogenesis, reduced respiratory capacity and features of exhaustion, thereby limiting the efficacy of immune checkpoint inhibitors (ICIs). In this review, we summarize current insights into the role of mitochondrial pathways in regulating tumor immune escape and T-cell dysfunction in CRC. We further discuss emerging therapeutic strategies aimed at targeting metabolic vulnerabilities to overcome resistance and potentially enhance responses to immunotherapy.
    Keywords:  T-cell exhaustion; cancer immunotherapy; colorectal cancer; immune checkpoint inhibitors; immune evasion; metabolic reprogramming; mitochondrial dysfunction; tumor microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2026.1908222
  6. Front Immunol. 2026 ;17 1756987
    Advances in IL-2-based cancer immunotherapy and the synergistic role of stem-like CD8+ T cells in IL-2 and PD-1 combination therapy.
    Huiquan Gao, Shubo Wang, Huiru Yuan, Bingxiu Zhou, Fuxin Zhou.
      IL-2 is a pleiotropic cytokine that plays a central role in the activation and proliferation of cytotoxic lymphocytes and regulatory T cells. Since its discovery in 1976 as a T-cell growth factor and its subsequent U.S. FDA approval for metastatic renal cell carcinoma and melanoma, IL-2 has represented a landmark in cancer immunotherapy. However, high-dose (HD) IL-2 therapy is associated with substantial toxicities, including vascular leak syndrome. Recent advances in structural and receptor biology have clarified the molecular mechanisms underlying IL-2's dual immunostimulatory and immunoregulatory effects. These discoveries have enabled the design of next-generation IL-2 variants (IL-2v) with improved pharmacokinetics, receptor selectivity, and safety profiles. Importantly, PD-1+ TCF-1+ stem-like CD8+ T cells have recently been identified as a key population sustaining long-term antitumor immunity. TCF-1 is a transcription factor associated with a less differentiated, self-renewing state and marks this progenitor-exhausted subset. By contrast, terminally exhausted T cells exhibit a highly differentiated, poorly proliferative state and limited capacity for functional reinvigoration, whereas progenitor-exhausted cells retain stem-like properties, self-renewal capacity, and responsiveness to therapy. Furthermore, these cells respond robustly to IL-2 and are central mediators of the synergy observed between IL-2 signaling and PD-1 blockade. Mechanistically, PD-1 inhibition releases inhibitory constraints, while IL-2 provides a potent STAT5-driven proliferative and differentiation signal that expands the stem-like CD8+ T-cell pool and generates functional effector CD8+ T cells. This review summarizes IL-2 biology, the limitations of high-dose IL-2 (HD IL-2) therapy, and emerging strategies, including CD25- or CD122-biased IL-2 variants, tumor-targeted IL-2 prodrugs, and IL-2-based combination therapies designed to harness IL-2's antitumor potential while minimizing systemic toxicity, with particular emphasis on the role of stem-like CD8+ T cells as key mediators of therapeutic efficacy.
    Keywords:  CD122 bias; CD25 bias; IL–2; IL–2 variants; cancer immunotherapy; cytokine engineering; immunocytokines; prodrugs of IL–2
    DOI:  https://doi.org/10.3389/fimmu.2026.1756987
  7. Front Cell Dev Biol. 2026 ;14 1914317
    Spatial proteomics: technical evolution and applications in cancer research.
    Xiaoxiao Tian, Di Huang, Jiaxiang Hu.
      Spatial proteomics is reshaping tissue-based cancer research by linking protein expression to cellular identity, tissue architecture and clinical behavior. Conventional proteomics has provided powerful tools for protein identification and quantification, but most bulk workflows erase the spatial relationships that define tumor ecology. In contrast, spatial proteomics combines multiplexed imaging, mass spectrometry-based tissue analysis, region-selected profiling and computational spatial statistics to measure proteins in their native tissue context. This review summarizes the development of proteomics from early separation and mass spectrometry technologies to current spatial platforms. It then focuses on cancer applications, including tumor heterogeneity, tumor microenvironment, antitumor immunity, immunotherapy response, spatial biomarkers and treatment resistance. Across these areas, spatial proteomics is most valuable when it converts descriptive tissue patterns into testable hypotheses about cell states, neighborhood interactions and therapeutic vulnerabilities. The field now needs standardized workflows, clinically anchored cohorts and functional validation to move from high-dimensional tissue maps to robust translational tools.
    Keywords:  cancer; mass spectrometry imaging; spatial biomarkers; spatial proteomics; tumor microenvironment
    DOI:  https://doi.org/10.3389/fcell.2026.1914317
  8. Nat Commun. 2026 09 06. pii: 10564. [Epub ahead of print]17(1):
    PRMT7 restricts CD8+ T cells expansion via the NF-ΚB pathway.
    Nivine Srour, Kaixiu Luo, David Allard, Yan Xiong, Zhenbao Yu, Theodore Papadopoulos, François Santinon, Cheng-Hsun Hsieh, Anthony Parent, John Stagg, Simon Turcotte, Dalia Barsyte-Lovejoy, Stéphanie Lehoux, Sonia V Del Rincón, Jian Jin, Stéphane Richard.
      Successful cellular immunotherapy for cancer utilising cytotoxic T lymphocytes (CTL) requires efficient expansion while maintaining effector function. Understanding how CTL expansion and function are regulated during the cell preparation process is thus important. Here, we show that T cell-specific deletion of Prmt7 using CD4-Cre increases CD8+ T cell effector differentiation, cytokine secretion, cytolytic activity and anti-tumor responses. Prmt7 deficiency transcriptionally reprograms CD8+ T cells by activating the NF-κB pathway, boosting proliferation, and facilitating the production of effector molecules such as CD25, CD69 and IFNγ. Mechanistically, PRMT7 associates with RelA and restricts RelA nuclear translocation. In vitro, a self-developed PRMT7-targeting PROTAC degrader, MS54, similarly activates the NF-κB pathway as in Prmt7-deficient CTL. In vivo, adoptive cell transfer of MS54-treated OT-I CTLs improves tumor control in a mouse syngeneic melanoma model. In human CTL, MS54 enhances proliferation, activation markers (CD69, CD137) expression, IFNγ production and cytotoxicity toward melanoma. Our findings thus identify PRMT7 as a negative regulator of CD8+ T cell immunity and highlight MS54 as a potential strategy to improve adoptive T cell therapy.
    DOI:  https://doi.org/10.1038/s41467-026-77155-2
  9. Front Immunol. 2026 ;17 1889313
    Metabolite-driven dysfunction of intratumoral tertiary lymphoid structures: single-cell and spatial omics perspectives on cancer immune escape.
    Yifeng Wang, Yan Li, Shujuan Wei, Shengguang Ding.
      Intratumoral tertiary lymphoid structures (TLSs) are increasingly recognized as spatially organized immune niches associated with favorable prognosis and improved responses to immune checkpoint blockade. Yet TLS positivity is not synonymous with durable antitumor immunity. Many tumors contain lymphoid aggregates that are anatomically visible but developmentally arrested, poorly vascularized, depleted of germinal center-like activity, or uncoupled from effective plasma-cell and T-cell output. This discrepancy has shifted the field from a binary TLS-positive/TLS-negative view toward a state-based interpretation of TLS competence. Here, we propose that metabolite-driven remodeling of the tumor microenvironment is a major cause of intratumoral TLS failure. However, the current literature lacks a cell-type- and spatially resolved framework linking individual metabolites to disruption of defined TLS modules and distinguishing early developmental deviation from later functional collapse. Single-cell and spatial omics now show that productive TLSs depend on coordinated interactions among stromal organizer cells, HEV-like endothelium, mature dendritic cells, T follicular helper-like cells, B-cell lineages, plasma cells, and stem-like or progenitor exhausted T cells. These cellular modules are vulnerable to oxygen limitation, nutrient competition, lactate accumulation, extracellular adenosine, tryptophan catabolism, vascular stress, and suppressive B-cell states. A central goal of this review is to establish a hierarchy of mechanistic certainty across the metabolic drivers of TLS dysfunction. Tryptophan metabolism currently has the strongest direct TLS-specific spatial and perturbational evidence, whereas lactate, adenosine, hypoxia-associated vascular stress, lipid stress, and nucleotide metabolism are supported mainly by convergent immunometabolic and spatial evidence. On this basis, we outline biomarker-guided strategies to restore TLS competence, including inhibition of tumor-derived tryptophan metabolism to promote TLS maturation and enhance anti-PD-1 efficacy.
    Keywords:  adenosine; high endothelial venules; lactate; single-cell RNA sequencing; spatial transcriptomics; tertiary lymphoid structures; tryptophan metabolism; tumor metabolism
    DOI:  https://doi.org/10.3389/fimmu.2026.1889313
This page is being maintained by Thomas Krichel. It was last updated on 2026‒10‒11 at 14:15.