Formic acid released by intratumoral Bacteroides thetaiotaomicron facilitates combinational therapy of Apatinib and aPD-1 in hepatocellular carcinoma

Through various murine models and 5R–16S sequencing, we identified Bacteroides thetaiotaomicron ( B.t ) as a sensitizer for the combined treatment of Apatinib and anti-PD-1 therapy. Clinically, B.t enrichment was associated with improved neoadjuvant treatment outcomes and a favorable prognosis in HCC patients. Mechanistically, B.t produces formic acid in tumor cells, inhibits aryl hydrocarbon receptor (AhR) nuclear translocation by methylation, and suppresses downstream pathways, thereby mitigating pro-angiogenic effects and immunosuppression. The addition of formate or AhR inhibitors with combined treatment significantly enhanced therapeutic efficacy in preclinical models.