Phocaeicola vulgatus induces immunotherapy resistance in hepatocellular carcinoma via reducing indoleacetic acid production.

Abstract

Immunotherapy has made remarkable achievements in various cancers, but response rates in hepatocellular carcinoma (HCC) remain highly variable. Understanding mechanisms behind this heterogeneity and identifying responsive patients are urgent clinical challenges. In this study, the metagenomic analysis of 65 HCC patients reveals distinct gut microbiota profiles distinguishing responders (Rs) from non-responders (NRs). These findings are further validated through fecal microbiota transplantation (FMT) in mouse models. Notably, Phocaeicola vulgatus (P. vulgatus) is enriched in NRs and diminishes anti-PD-1 efficacy in both syngeneic and orthotopic tumor models. Mechanistically, P. vulgatus suppresses the production of indoleacetic acid (IAA), thereby weakening interferon (IFN)-γ⁺ and granzyme B (GzmB)⁺CD8⁺ T cells and impairing the antitumor immune response. Furthermore, supplementation with IAA restores CD8⁺ T cell cytotoxicity and counteracts the immune-suppressive effects of P. vulgatus. Our findings establish a causal relationship between P. vulgatus and anti-PD-1 resistance in HCC, highlighting IAA as a potential therapeutic target to enhance immunotherapy outcomes.