Obesity-derived metabolites modulate anti-tumor immunity in the tumor microenvironment: from mechanisms to clinical applications

The tumor microenvironment (TME) is increasingly understood as a metabolically dynamic ecosystem in which local metabolite availability, composition, and trafficking shape immune cell fitness and therapeutic responsiveness. Against the backdrop of the global obesity epidemic, obesity-associated systemic metabolic dysregulation has been implicated in tumor initiation and progression and may also influence the immune contexture and treatment responsiveness of tumors. This Review examines how obesity-derived systemic metabolites may modulate anti-tumor immunity and influence cancer immunotherapy, with particular emphasis on pathways involved in metabolic reprogramming and TME remodeling. We further discuss intervention strategies spanning (i) upstream metabolite generation, (ii) systemic-to-local trafficking into the TME, and (iii) direct functional antagonism within the TME. However, the available evidence remains heterogeneous across metabolite classes, tumor types, and experimental contexts, and this heterogeneity is likely to contribute to divergent immunotherapeutic phenotypes, including obesity-associated heterogeneity in immune checkpoint blockade (ICB) responsiveness. By integrating these layers into a source-to-sink framework, we highlight translationally relevant directions for understanding how systemic metabolites may reshape the metabolic niche of the TME and for informing more precise, context-aware, and safety-conscious metabolite-directed strategies in cancer immunotherapy.