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Updated: Sep 10, 2025

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

Xuetao Lei1,2,3, Boyang Zheng1,4,2, Yanmei Peng5,6

  • 1Department of General Surgery & Nanfang Gastrointestinal Cancer Institute (NGCI), Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong 510515, P. R. China.

International Journal of Biological Sciences
|August 27, 2025
PubMed

Insights

Researchers discovered a new pathway involving NAT10 that causes abnormal tumor blood vessels in gastric cancer. Inhibiting this pathway normalizes vasculature and enhances anti-cancer immune responses, improving immunotherapy effectiveness.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Tumor vascular normalization is a strategy to improve anti-cancer immune therapies.
  • Gastric cancer (GC) often exhibits abnormal tumor vasculature, hindering treatment efficacy.

Purpose of the Study:

  • To identify novel mechanisms driving vascular abnormalization in GC.
  • To explore therapeutic strategies targeting tumor vasculature and the immune microenvironment.

Main Methods:

  • Integrative analysis of acetylated RNA immunoprecipitation sequencing (acRIP-seq).
  • Functional validation using genetic and pharmacological inhibition.
  • Assessment of tumor vasculature, immune cell infiltration, and anti-tumor efficacy in syngeneic GC models.

Main Results:

  • A novel NAT10/XIST/YAP1/VEGFA signaling axis was identified as a driver of vascular abnormalization in GC.
  • NAT10 inhibition stabilized tumor vasculature and reshaped the immune microenvironment by upregulating chemokines and promoting cytotoxic lymphocyte infiltration.
  • Combination therapy of NAT10 inhibition (Remodelin) and YAP1 inhibition (Verteporfin) synergistically enhanced anti-PD-1 efficacy, suppressing tumor growth.

Conclusions:

  • Discovered an ac4C-dependent epitranscriptomic mechanism regulating vascular-immune crosstalk in GC.
  • Propose a novel combinatorial therapeutic strategy targeting NAT10 and YAP1 to overcome resistance to immune checkpoint blockade in GC.
Keywords:
NAT10XISTYAP1gastric cancervascular normalization

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