Metabolic Constraints and Interactions Drive T-cell Function and Exhaustion in Cancer Progression

The efficacy of immunotherapy against solid tumors is often limited by the need for T cells to function properly within the metabolically hostile tumor microenvironment (TME). Within this context, tumor-infiltrating T cells face immunosuppressive cues, cellular competition, and metabolic stress that reshape their bioenergetic demands and compromise their anti-tumor activity. Specific metabolic features, such as enhanced glycolysis and altered lipid metabolism, shaped by immunoediting, create conditions that promote immune evasion. Notably, different T-cell subsets exhibit distinct metabolic profiles, with fatty acids playing essential roles in energy production, signaling, and survival during cancer development. Contemporary therapeutic strategies seek to enhance T-cell cytotoxicity by targeting metabolic pathways or reprogramming genes involved in metabolic symbiosis. However, clinical translation is challenged by the complex interplay between metabolism and immune functions. Emerging evidence has highlighted lipid metabolism as a key systemic regulator of both immune activation and suppression, positioning it as a promising target for intervention. This review summarizes key insights into T-cell metabolic reprogramming in the TME, explores novel immunometabolic strategies, and outlines the challenges and future directions for translating these findings into durable cancer immunotherapies.