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Abstract

Programmed cell death protein 1 (PD-1), an immune checkpoint primarily expressed on T cells, plays a critical role in mediating tumor immune evasion. However, the role of PD-1 in non-immune cells remains poorly understood. Here, we report tumor cell-intrinsic PD-1 expression in malignant ascites from ovarian cancer patients. Using murine ovarian cancer models, we demonstrate that PD-1 directly promotes ovarian cancer progression. Moreover, malignant ascites markedly upregulates PD-1 expression in ID8 ovarian cancer cells, acting as a pathological amplifier that exacerbates PD-1-mediated oncogenic signaling cascades, including enhanced proliferation and metastasis both in vitro and in vivo. Mechanistically, soluble PD-L1 (sPD-L1) in ascites interacts with tumor cell-intrinsic PD-1, activating the MAPK/ERK signaling pathway through enhanced phosphorylation of ERK1/2. In contrast, PD-1 inhibition, achieved by genetic knockout or antibody blockade, reverses these tumor-promoting effects. Furthermore, pharmacological inhibition of phosphorylated ERK1/2 counteracts the tumor progression mediated by the PD-1 and prolongs survival in murine ovarian cancer models. Our study uncovers a previously unrecognized tumor-intrinsic PD-1-ERK signaling axis in ovarian cancer, that accelerates tumorigenesis and provides new insights and perspectives for PD-1/PD-L1 immune checkpoint therapy in ovarian cancer.