CRACD loss drives hypoxia-induced immune escape in gastric cancer

Abstract Mucinous gastric adenocarcinoma (MGC) is a distinct histologic subtype characterized by poor prognosis and limited responsiveness to chemotherapy and immunotherapy. CRACD, an actin polymerization regulator, is frequently inactivated in gastric cancer (GC), with enrichment in mucinous subtypes. We found that genetic engineering of murine gastric organoids with Cracd ablation combined with Kras mutation and Trp53 loss induced mucinous cell plasticity, disrupted epithelial integrity, and promoted immune evasion. Mechanistically, CRACD loss triggered actin dysregulation, which activated the NF-kB/COX2 signaling and NADPH oxidase-dependent ROS generation. The resulting oxidative stress stabilized HIF1α and transactivated PD-L1 , thereby disrupting anti-tumor immunity. Pharmacologic inhibition of HIF1α or PD-L1 restored immune surveillance and suppressed tumorigenesis. Clinically, analysis of patient-derived organoids and tissue microarrays demonstrated the inverse correlation between CRACD and PD-L1 expression. These findings identify CRACD inactivation as a crucial event in mucinous plasticity and immune escape in GC, further proposing that the HIF1α-PD-L1 axis is a therapeutic vulnerability in CRACD-inactivated GC.