Urolithin A blocks colorectal cancer progression by AKT1 inhibition-driven immune activation.

Colorectal cancer (CRC) is one of the most common and lethal malignancies worldwide, with its initiation and progression closely linked to metabolic reprogramming, abnormal cell proliferation, and immune evasion. Urolithin A (UA), a natural polyphenol with favorable oral safety and bioavailability, has been reported to exert antitumor effects through metabolic regulation and immune modulation. In this study, we combined network pharmacology, molecular docking, and single-cell transcriptomics to explore the potential anticancer mechanisms of UA, which were further examined through in vitro and in vivo experiments. UA was found to be associated with AKT1-related signaling and dose-dependently suppressed the proliferation, migration, and invasion of CRC cell lines, including HCT15, HCT116, and MC38. At appropriate concentrations, UA further enhanced CD8+ T-cell proliferation, differentiation toward an effector-like phenotype, and cytotoxic activity. In an orthotopic CRC mouse model, oral UA treatment markedly inhibited tumor growth and promoted intratumoral CD8+ T-cell infiltration. Mechanistically, UA was associated with modulation of the AKT/mTOR signaling pathway to limit tumor progression and with alterations in AKT1-related signaling, including changes in the P-AKT1/FOXO1 axis and increased expression of cytotoxic effector molecules such as GZMB, thereby contributing to antitumor immune activation and remodeling of the tumor immune microenvironment. This study proposes a working model of a diet-microbiota-AKT1-immunity axis, which may provide conceptual insights into CRC prevention and immunotherapeutic strategies.