KAT2B acetylates YTHDF2 to drive immune evasion in pancreatic ductal adenocarcinoma

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is largely refractory to immune checkpoint blockade, yet the tumor cell-intrinsic programs that sustain immune evasion remain incompletely understood. Here, using parallel in vivo CRISPR–Cas9 screens in immunocompetent and immunodeficient hosts, we identify the lysine acetyltransferase KAT2B as an adaptive immunity-dependent fitness factor in KRAS-mutant PDAC. KAT2B loss enhances intratumoral CD8⁺ T cell accumulation and effector activity and restricts tumor growth in an adaptive immunity-dependent manner. Mechanistically, KAT2B directly acetylates the m6A reader YTHDF2 at K440, K521, and K562. This modification enhances YTHDF2 association with m6A-modified RNA and promotes DDX58 mRNA decay, thereby attenuating RIG-I–TBK1–IRF3 signaling and tumor cell-intrinsic antiviral immunity; disruption of this acetylation restores antiviral signaling and antitumor immune activity. Pharmacologic targeting of YTHDF2 suppresses PDAC growth and enhances responses to KRAS inhibition and PD-1 blockade in preclinical models. Together, our findings define a nonhistone KAT2B–YTHDF2 acetylation axis that links protein acetylation to m6A-dependent RNA decay and antiviral tumor immunity, revealing a therapeutically actionable vulnerability in PDAC.

ORGANISM(S): Mus musculus

PROVIDER: GSE352671 | GEO | 2026/11/03

REPOSITORIES: GEO