bims-spamet 2026-08-02 papers

Curr Opin Immunol. 2026 Jul 29. pii: S0952-7915(26)00106-8. [Epub ahead of print]102 102829

Spatial metabolic heterogeneity shapes CD8+ T cell function in cancer.

Tumors are spatially heterogeneous ecosystems in which malignant, stromal, vascular, and immune cells interact within metabolically distinct niches. These localized microenvironments are shaped by factors such as nutrient availability, hypoxia, acidosis, and immunomodulatory metabolites, all of which strongly influence CD8⁺ T cell infiltration, migration, persistence, and effector function. Growing evidence indicates that spatial metabolic heterogeneity contributes to immune exclusion, T cell dysfunction, and resistance to immunotherapy. This has been accompanied by major advances in spatial metabolomics, particularly mass spectrometry imaging, which now enable the in situ mapping of metabolites within intact tissues. Combined with transcriptomic, proteomic, and imaging-based approaches, these technologies provide unprecedented insight into how metabolism is organized across tumors and how it shapes tumor-immune interactions. In this review, we discuss how metabolic zonation shapes CD8⁺ T cell function across primary tumors and metastatic lesions. We highlight emerging evidence linking localized metabolic programs to T cell exhaustion, impaired motility, and altered immune composition, and discuss therapeutic strategies aimed at improving T cell metabolic fitness, including metabolic modulation and engineering approaches relevant to immune checkpoint blockade and adoptive cell therapies. Finally, we consider the translational potential of spatial metabolomics for biomarker discovery and the development of precision immunometabolic oncology.

DOI: https://doi.org/10.1016/j.coi.2026.102829

Trends Immunol. 2026 Jul 31. pii: S1471-4906(26)00181-X. [Epub ahead of print]

Targeting the fate of exhausted CD8+ T cells.

Daniel T Utzschneider, Stephen J Turner.

CD8+ T cell exhaustion is increasingly recognized as a regulated adaptation to chronic antigenic stimulation rather than a simple immune failure. Indeed, recent studies reveal that exhaustion is imprinted early after T cell activation, integrating transcriptional and epigenetic cues to balance effector function with long-term persistence. Key regulators, including Inhibitor of DNA binding 3 (ID3), Thymocyte selection high mobility box protein (TOX), MYB, Krüppel-like factor 2 (KLF2), and Special AT-rich sequencing binding protein 1 (SATB1), orchestrate this process, preserving stem-like precursor populations that sustain immunity during chronic infection and cancer. This emerging view frames exhaustion as a context-dependent extension of the memory program rather than its collapse. By defining the molecular and functional logic of exhaustion, we highlight how these insights can inform new approaches to manipulate T cell fate for therapeutic benefit.

DOI: https://doi.org/10.1016/j.it.2026.07.002

Redox Biol. 2026 Jul 25. pii: S2213-2317(26)00321-6. [Epub ahead of print]96 104322

Deoxycholic acid impairs mitochondrial fitness and suppresses mitophagy through Parkin ubiquitination driving CD8+ T cell Exhaustion in Colorectal Cancer.

Yang Gao, Jiaxin Wang, Shihui Lai, Mingwei Li, Jiaqi Shi, Xianjun Li, Ying Guo, Sainan Ma, Xinxin Wang, Shule Zhang, Tianyu He, Yu Hong, Shuang Li, Caiqi Liu, Lijuan Cao, Haiping Hao, Chujie Ding.

Colorectal cancer (CRC) exhibits significant heterogeneity in response to immunotherapy that cannot be fully explained by microsatellite status alone. Although elevated bile acid levels are recognized as an important risk factor for CRC, their impact on immunotherapy responsiveness remains poorly understood. Here, we demonstrate that high bile acid levels profoundly impair anti-PD-1 efficacy in both CRC patient cohort and mouse models, accompanied by reduced infiltration and functional impairment of tumor-infiltrating CD8+ T cells. Bile acid profiling identified deoxycholic acid (DCA) as the key bile acid species mediating this immunosuppressive effect. In vitro and in vivo studies have shown that DCA not only suppressed CD8+ T cell effector function but also drove them toward terminal exhaustion, thereby limiting responsiveness to anti-PD-1. Mechanistically, DCA disrupted mitochondrial fitness in CD8+ T cells by suppressing oxidative phosphorylation and inducing excessive mitochondrial reactive oxygen species (mtROS) production. In parallel, DCA enhanced ubiquitination-dependent degradation of Parkin, thereby inhibiting mitophagy and causing the accumulation of damaged mitochondria. These convergent defects in mitochondrial homeostasis ultimately promoted CD8+ T cell dysfunction and terminal exhaustion. Notably, pharmacological reactivation of mitophagy via Urolithin A reversed these defects and restored the antitumor efficacy of anti-PD-1 in vivo. Collectively, our findings identified a DCA-Parkin-mitophagy axis that drives CD8+ T cell terminal exhaustion and compromises immunotherapy efficacy, providing a potential metabolic intervention strategy to improve immunotherapy responses in CRC patients with elevated bile acid levels.

Keywords: Anti-PD-1 therapy; CD8(+) T cell terminal exhaustion; Colorectal cancer; Deoxycholic acid; Mitochondrial dysfunction; Mitophagy

DOI: https://doi.org/10.1016/j.redox.2026.104322

Int J Biol Sci. 2026 ;22(12): 6338-6362

Glycosylation of B7-H3 Promotes CD8+ T Cell Exhaustion by Inhibiting the Endosome-Lysosome Pathway in HCC.

Yifan Yu, Jiaxing Liu, Zhixiong Hao, Yu Li, Guangpeng He, Xuzhe Wang, Liang Yang, Xiaodan Liu, Hangyu Li, Xueqiang Peng.

A pivotal factor in the immune evasion of hepatocellular carcinoma (HCC) is the excessive exhaustion of CD8+ T cells; however, the molecular drivers of this phenomenon remain incompletely understood. In this study, we discovered that B7-H3 is markedly overexpressed in HCC and actively promotes CD8+ T cell exhaustion. Through high-resolution mass spectrometry and site-directed mutagenesis, we identified asparagine 215 (N215) as a critical N-linked glycosylation site of B7-H3. By employing dual orthogonal strategies-pharmacological inhibition via tunicamycin and targeted genetic ablation (N215Q mutation)-we provided strong evidence that, upon N215 glycosylation, B7-H3 maintains its cell-surface abundance through RAB11-mediated recycling of the endosomal pathway. Conversely, when glycosylation is impeded through either intervention, B7-H3 undergoes accelerated degradation via the endosome-lysosome route, thereby enhancing the cytotoxic activity of CD8+ T cells. Finally, murine experiments confirmed that both the specific genetic disruption of N215 and systemic blockade with tunicamycin enhance the antitumor effects of anti-PD-1, anti-PD-L1, and anti-CTLA-4 antibodies. Collectively, our data reveal that the "B7-H3 Glycosylation-RAB11 Axis" preserves membrane expression of B7-H3, constituting an intrinsic mechanism of immune evasion in HCC, and uncover the intricate crosstalk between B7-H3 glycosylation and the immunosuppressive tumor microenvironment.

Keywords: B7-H3; CD8+ T cell exhaustion; hepatocellular carcinoma; tumor microenvironment

DOI: https://doi.org/10.7150/ijbs.126547