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T cell metabolism shapes immune function, but how CD8+ T cell flexibility relates to immunotherapy response is unclear. Using spatial proteomics, we map a metabolic continuum of tumor-infiltrating CD8+ T cells defined by differential fermentative and oxidative engagement. These states display distinct immune interactomes and metabolic niches, reflecting lineage-transcending regulator patterns. Metabolic flexibility, such as lactate utilization, characterized responder tumors and correlated with enriched memory and progenitor-exhausted signatures in transcriptomic datasets. Machine learning integration of metabolic and immunological profiles predicted checkpoint blockade response. Our findings position metabolic flexibility, not abundance, as central to durable antitumor immunity.
