Circ_0005406 Promotes Ovarian Cancer Progression through IL-33-Dependent Recruitment of Tumor-Associated Macrophages

Ovarian cancer (OC) is a highly lethal malignancy with limited therapeutic options. Multiple peptides encoded by non-coding RNAs have exhibited critical anti-tumor activities. Through integrated RNC-seq and MeRIP-seq analyses, we identified circ_0005406 as a circRNA with translational potential. This study aims to elucidate the role and mechanism of circ_0005406 in OC progression and evaluate its potential as a therapeutic target. Circ_0005406 was downregulated in OC tissues compared to normal ovarian epithelium. Its overexpression robustly promoted orthotopic tumor growth in mice, despite exerting minimal proliferative effects in vitro. Integrated RNA-seq and co-culture studies revealed that this pro-tumorigenic phenotype was driven by an immunosuppressive microenvironment, characterized by IL-33 upregulation and increased M2 macrophage infiltration. Mechanistically, the m6A reader IGF2BP2 was identified as a central regulator that binds circ_0005406 to enhance its translation and stabilizing IL33 mRNA. Knockdown of IGF2BP2 abrogated macrophage chemotaxis. Besides, circ_0005406 may encodes a nuclear-localized 275-amino-acid peptide. Circ_0005406 promotes OC progression by recruiting M2 macrophages via IL33. Mechanistically, IGF2BP2 acts as a nexus that concurrently boosts circ_0005406 translation and stabilizes IL33 mRNA, a dual action that synergistically drives macrophage infiltration.