A mediterranean-mimicking diet harnesses gut microbiota-derived 3-IAA to rejuvenate T cell

Abstract

Diet profoundly shapes the tumor microenvironment through metabolite modulation, yet the mechanisms linking diet, gut microbiota, and antitumor immunity remain unclear. Here, we demonstrate that a mediterranean-mimicking diet (MedDiet) suppresses tumor growth by orchestrating a microbiota-metabolite-immune axis. MedDiet selectively enriched Bacteroides thetaiotaomicron (B. thetaiotaomicron) in the gut, whose administration recapitulated tumor suppression. Both MedDiet and B. thetaiotaomicron elevated plasma levels of the tryptophan metabolite indole-3-acetic acid (3-IAA). Mechanistically, 3-IAA enhanced CD8+ T cell cytotoxicity and alleviated exhaustion by inhibiting the integrated stress response, sustaining antitumor immunity in vivo. Importantly, 3-IAA synergized with anti-PD-1 therapy to further restrain tumor progression. Finally, we developed a MedDiet Score to predict patient survival and response to immunotherapy. These findings reveal that dietary modulation of gut microbiota can reshape systemic metabolites to potentiate T cell-mediated antitumor responses. Our study identifies 3-IAA as a metabolite-based adjuvant for immune checkpoint therapy and highlights the translational potential of diet-driven immunomodulation in cancer treatment.