Targeting the NAT10/XIST/YAP1 Axis-Mediated Vascular Abnormalization Enhances Immune Checkpoint Blockade in Gastric Cancer.

Abstract

Tumor vascular normalization has emerged as a promising strategy to potentiate immune checkpoint blockade in solid tumors. Here, we unveil a previously unrecognized NAT10/XIST/YAP1/VEGFA signaling axis driving vascular abnormalization in gastric cancer (GC) and demonstrate its therapeutic potential in remodeling the tumor immune microenvironment. Through integrative analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq) and functional validation, we identified NAT10-mediated N4-acetylcytidine (ac4C) modification as a critical stabilizer of lncRNA XIST. Mechanistically, XIST recruits hnRNPK to facilitate YAP1 nuclear translocation, thereby activating TEAD4-dependent VEGFA transcription and promoting angiogenic programming. Genetic or pharmacological inhibition of NAT10 with Remodelin attenuated VEGFA secretion, enhanced pericyte coverage and basement membrane integrity, and normalized tumor vasculature in syngeneic GC models. Moreover, we found that NAT10 inhibition reshaped the immune landscape by upregulating CXCL9/10/11 chemokines, promoting cytotoxic lymphocyte infiltration while reducing Treg populations. Strikingly, combining Remodelin with the YAP1 inhibitor Verteporfin synergistically augmented anti-PD-1 efficacy, significantly suppressing tumor growth in immunocompetent mouse models. Our findings not only elucidate an ac4C-dependent epitranscriptomic mechanism governing vascular-immune crosstalk but also propose a novel combinatorial therapeutic strategy to overcome resistance to immune checkpoint blockade in GC.