CC chemokines in epithelial ovarian cancer: orchestrating the metastatic microenvironment and therapy resistance

Peritoneal metastasis is a major contributor to progression, recurrence, and treatment failure in epithelial ovarian cancer (EOC) and is closely associated with dynamic remodeling of the peritoneal tumor microenvironment (TME). Interactions among tumor cells, ascites, the omental niche, stromal components, and immune cells collectively shape metastatic dissemination and therapeutic response. CC chemokines are important regulators of these processes, linking immune-cell trafficking with tumor-cell plasticity, metabolic adaptation, angiogenesis, and therapy resistance. This review summarizes the roles of CC chemokines in EOC progression within a chemokine-driven peritoneal niche remodeling framework encompassing four key stages: early dissemination, survival in ascites, omental colonization, and therapy resistance. Among the major signaling axes, CCL2-CCR2 is primarily associated with monocyte recruitment and myeloid-dominant immunosuppression, whereas CCL5-CCR5 is linked to stromal immune regulation and cancer stem-like phenotypes. Additional pathways, including CCL18, CCL20-CCR6, CCL22-CCR4, and CCL1-CCR8, contribute to T-regulatory cell recruitment, immune suppression, and hypoxia-associated responses. The review further discusses the limited efficacy of chemokine-targeted monotherapy, highlighting challenges posed by signaling redundancy, compensatory pathways, spatial heterogeneity, and insufficient biomarker-guided patient selection. Recent advances in single-cell and spatial transcriptomic technologies have improved the characterization of compartment-specific chemokine programs within the EOC microenvironment. Finally, emerging combination strategies involving chemokine blockade together with immune checkpoint inhibitors, metabolic interventions, PARP inhibitors, and ferroptosis-related approaches are evaluated. However, successful clinical translation will require precise patient stratification, effective toxicity management, and validation in clinically annotated cohorts.