Indole‐3‐Propionic Acid Drives Dendritic <scp>H3K27</scp> Acetylation to Enhance <scp>CD8</scp> + T Cell Immunity in Hepatocellular Carcinoma

ABSTRACT Indole‐3‐propionic acid (IPA) is documented to improve the effectiveness of tumor immunotherapy via regulating anti‐tumor immunity. However, the impacts of IPA in hepatocellular carcinoma (HCC) patients undergoing sintilimab combined with bevacizumab (SCB) treatment remain unknown. This study investigated the effects and underlying mechanisms of IPA in SCB‐treated HCC. Serum, tumor tissue, fecal and lymph node tissue samples were collected from HCC patients with or without a response to SCB therapy. Humanized orthotopic and subcutaneous HCC NOG mouse models were established. IPA‐treated mouse dendritic cells (DCs) were co‐cultured with mouse CD8 + T‐cells, which were subsequently co‐cultured with Hepa1‐6 cells. IPA levels were elevated in the serum, tumor tissues, and feces of responders, and serum IPA levels were positively correlated with the proportion of IFN‐γ + CD8 + T cells in tumor tissues as well asac‐H3K27 and IL‐12A levels in lymph node DCs. IPA amplified the suppressive impact of SCB on tumor growth in HCC mice. Moreover, IPA increased ac‐H3K27 and IL‐12A levels in DCs and upregulated effector CD8 + T‐cell immunity in HCC mice. Administration of a CD8‐neutralizing antibody and injection of shIL‐12A‐transfected DCs weakened IPA‐mediated inhibition of HCC in vivo. Furthermore, the ac‐H3K27 inhibitor A‐485 suppressed IL‐12A expression and effector CD8 + T‐cell immunity induced by IPA, thereby promoting the proliferation, invasion, and migration of Hepa1‐6 cells in vitro. These findings demonstrate that IPA enhances the effect of SCB‐treated HCC by upregulating H3K27 acetylation to promote IL‐12A expression in DCs, thereby potentiating CD8 + T‐cell immunity, which provides a basis for its potential use as a clinical adjuvant therapy.