Targeting m ⁶ A Reader YTHDF1 Enhances Antitumor Immunity and Potentiates Anti‐PD‐L1 Efficacy in Intrahepatic Cholangiocarcinoma

ABSTRACT The N6‐methyladenosine (m ⁶ A) 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 m ⁶ A‐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 m ⁶ A 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.