Abstract

Immunosuppression in ovarian cancer is primarily driven by myeloid-derived suppressor cells (MDSCs). This study identifies karyopherin α2 (KPNA2) as a novel regulator of this immunosuppressive process through the NF-κB/CCL2/CCR2 axis. Elevated KPNA2 expression correlates with increased intratumoral MDSC accumulation and impaired CD8+ T-cell function. Mechanistically, KPNA2 directly binds to and facilitates nuclear translocation of NF-κB/p65, thereby driving CCL2 transcription, while also exhibiting an auxiliary, p65-independent function in CCL2 induction. Secreted CCL2 recruits MDSCs in a CCR2-dependent manner, establishing a potent immunosuppressive tumor microenvironment. Therapeutic targeting via MDSC depletion, pharmacological CCR2 blockade, or direct KPNA2 knockdown effectively inhibited metastasis, enhanced CD8+ T-cell infiltration, and suppressed tumor growth. Importantly, CCR2 inhibition synergized with anti-PD-L1 therapy, revealing a promising combination immunotherapeutic strategy for KPNA2-high ovarian cancer. These findings establish the KPNA2-governed NF-κB/CCL2/CCR2 pathway as a central mechanism of immune evasion and a viable target for combination immunotherapy in ovarian cancer.