Claudin-4 as a dual regulator of genome stability and immune evasion in high grade serous ovarian cancer

High-grade serous carcinoma (HGSC) thrives in an immune-suppressive microenvironment marked by poor T-cell infiltration and blunted anti-tumor responses, driving immune evasion, tumor progression, and therapy resistance. Regulation of genomic instability, which restricts cytoplasmic DNA accumulation, is essential to prevent immune activation. Claudin-4, often overexpressed in HGSC, is strongly linked to therapy resistance and plays a key role in regulating initiation and resolution of genomic instability, shaping the tumor's potential ability to evade immune surveillance and withstand treatment; however, its role in immune evasion remains unclear. We used in vitro ovarian cancer models with stable claudin-4 overexpression and knockdown. In a humanized mouse model, ovarian tumors were treated with the claudin mimic peptide (CMP) and a PARP inhibitor. Tumor growth and immune infiltration were assessed by IVIS imaging and spectral flow cytometry. Mechanistic studies included autophagy flux and ISRE reporter assays, complemented by immunoblotting, flow cytometry, confocal microscopy, and bioinformatic analyses of public datasets. We identified a novel claudin-4-driven mechanism that promotes immune evasion in HGSC. Claudin-4 regulated type I interferon signaling through a close association with the small GTPase Rab7, modulating tumor-immune interactions. This was linked to TCR-zeta chain suppression in T cells in vivo-a hallmark of immune evasion. Dual targeting of claudin-4-expressing tumors with CMP and niraparib reshaped the tumor immune microenvironment, restoring TCR-zeta expression and promoting CD8 + T-cell infiltration, leading to improved anti-tumor efficacy of the PARP inhibitor niraparib. Our data show that claudin-4 orchestrates tumor immune evasion and survival, positioning it as a dual regulator of genome stability and immune escape, and highlighting it as a promising therapeutic target in ovarian cancer.