RORγ Hijacks HIF1α to Promote Peritoneal Metastasis of Gastric Cancer

Peritoneal metastasis (PM) is the most common and lethal form of metastasis in gastric cancer, highlighting an urgent need for treatment strategies. In this study, we identified retinoic acid receptor-related orphan receptor gamma (RORγ) as a key driver of PM in gastric cancer tumors. Integrative bioinformatics and IHC analyses revealed aberrant upregulation of RORγ in gastric cancer tumors, particularly in metastatic lesions. Functionally, elevated RORγ promoted gastric cancer cell adaptation to hypoxia and accelerated PM formation in vivo. The hypoxic microenvironment in gastric cancer stimulated RORγ expression, which in turn enhanced hypoxia-inducible factor 1α (HIF1α) stability, establishing a positive feedforward loop. Mechanistically, RORγ interacted with HIF1α and protected it from binding to proline hydroxylase domain 3 and von Hippel-Lindau, resulting in markedly decreased HIF1α hydroxylation and ubiquitylation and increased HIF1α accumulation, nuclear translocation, and transactivation. The RORγ-HIF1α complex bound to and activated target genes involved in the hypoxic response and epithelial-to-mesenchymal transition, thereby driving gastric cancer tumor growth and PM. Disruption of the RORγ-HIF1α interaction using RORγ antagonists markedly promoted HIF1α degradation and diminished its function. Importantly, in multiple gastric cancer xenograft models, RORγ inhibition effectively blocked tumor growth and PM while sensitizing tumors to chemotherapy. Thus, this study uncovers a mechanism of hypoxia-mediated metastasis through a RORγ-HIF1α reciprocal regulatory loop and offers a potential therapeutic option against PM in advanced cancer. SIGNIFICANCE: RORγ drives peritoneal metastasis in gastric cancer and can be targeted to block metastatic progression, suggesting that RORγ inhibition could serve as a therapeutic strategy for advanced gastric cancer.