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

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.