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.