Targeting mA Reader YTHDF1 Enhances Antitumor Immunity and Potentiates Anti-PD-L1 Efficacy in Intrahepatic Cholangiocarcinoma.

The N6-methyladenosine (mA) reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) plays a critical role in the tumorigenesis of intrahepatic cholangiocarcinoma (ICC), but its function in the tumor immune microenvironment remains unclear. RNA sequencing analysis of human ICC samples revealed that, among mA-related regulators, YTHDF1 exhibited the most significant negative correlation with immune score. In multiple ICC mouse models, Ythdf1 overexpression enhanced the recruitment of myeloid-derived suppressor cells (MDSCs) and suppressed cytotoxic CD8 T cell responses, promoting ICC progression. Immunostaining of human ICC tissue microarray verified that high YTHDF1 protein expression was significantly associated with increased accumulation of MDSCs and decreased infiltration of CD8 T cells. Mechanistically, YTHDF1 bound to the mA site of FOSL2 mRNA and promoted the translation of FOSL2, a transcription factor driving cytokine CXCL6 expression. Consequently, elevated CXCL6 recruited and activated MDSCs by binding to its receptor CXCR2, leading to the dysfunction of CD8 T cells in ICCs. In addition, targeting YTHDF1 alongside blockade of its downstream chemokine pathway enhanced the efficacy of anti-PD-L1 treatment in preclinical ICC mouse models, serving a promising strategy for improving immunotherapy efficacy in ICC.