Inhibition of circulating glycocholic acid-regulated signaling potentiates immune checkpoint therapy in colorectal cancer

Serum bile acids (BAs) are an important risk factor for the initiation and progression of cancer, but their roles in colorectal cancer (CRC) remain largely unknown. The present study showed that glycocholic acid (GCA), a primary BA, was highly accumulated in the serum of patients with CRC. In a mouse model of CRC, GCA diet promoted programmed death-ligand 1 (PD-L1) expression in tumors, which attenuated CD8+ T cell-mediated antitumor responses in the tumor microenvironment (TME), and promoted the occurrence and development of CRC. Increased PD-L1 expression was caused by the reduction in activity of the BA receptor farnesoid X receptor (FXR). Mechanistically, FXR acted as transcriptional repressor for the transcription factor SRY-box transcription factor 14 (SOX14), and suppressed the palmitoylation and stabilization of PD-L1 by inhibiting the SOX14-mediated expression of zinc finger DHHC-type palmitoyl transferase 9 (DHHC9). Notably, genetically silencing SOX14 and DHHC9 in cancer cells or administering an FXR agonist synergized with anti-PD-1 therapy, leading to reduced tumor growth in GCA-fed mice. Together, the present findings reveal a previously unrecognized mechanism of BA in remodeling the TME to mediate CRC resistance to immunotherapy, which may have clinical implications for developing immunotherapy strategies for patients with CRC.