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.