PD-L1 in Ovarian Cancer: Immune Evasion, Tumor-Intrinsic Signaling, and Chemoresistance.

Abstract

Epithelial ovarian cancer remains a lethal malignancy, primarily due to late-stage presentation and the frequent development of platinum resistance. While immune checkpoint blockade (ICB) targeting the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has revolutionized oncology, its success in ovarian cancer has been strikingly limited. This review synthesizes emerging evidence that extends the role of PD-L1 beyond canonical immune evasion to include tumor-cell-intrinsic mechanisms that may contribute to chemoresistance. We explore the "dual shield" function of PD-L1, detailing how its non-canonical, intracellular signaling promotes tumor cell survival, stemness, and therapy resistance. Mechanistically, preclinical studies indicate that PD-L1 can modulate DNA damage responses and may enhance anti-apoptotic signaling, rewire cellular metabolism, and regulate autophagy. Nuclear PD-L1 has also been linked to DNA repair machinery in preclinical cancer models, suggesting a potential mechanism of resistance to DNA-damaging therapy; however, direct mechanistic evidence in ovarian cancer remains limited and is still emerging. The tumor microenvironment further amplifies this axis through cytokine networks and physical barriers. These tumor-intrinsic survival mechanisms may help explain why PD-1/PD-L1 blockade alone has shown limited efficacy in ovarian cancer. Overcoming this requires rational combination strategies that simultaneously disrupt PD-L1-mediated immune suppression and its cell-autonomous pro-survival functions. Overall, this dual-function framework positions PD-L1 as a multifunctional therapeutic node and provides a rationale for combination strategies targeting both immune escape and tumor-intrinsic resistance mechanisms.