CC Chemokines Orchestrate Ovarian Cancer Metastasis and Therapy Resistance by Remodeling the Peritoneal Microenvironment

Epithelial ovarian cancer (EOC) is a highly lethal gynecological malignancy, with peritoneal metastasis being a primary driver of progression, recurrence, and treatment failure. Despite initial high response rates to platinum-taxane chemotherapy, most advanced-stage tumors recur with reduced sensitivity. The dynamic remodeling of the peritoneal tumor microenvironment (TME), involving complex interactions between tumor cells, ascites, the omental niche, stromal components, and immune cells, is crucial for metastatic dissemination and therapeutic response. Understanding these orchestrating factors, like CC chemokines, is vital for overcoming therapy resistance and improving patient outcomes.

This comprehensive review synthesized current knowledge on the roles of CC chemokines in epithelial ovarian cancer (EOC) progression. It specifically focused on how these chemokines drive peritoneal niche remodeling across four key stages: early dissemination, survival in ascites, omental colonization, and therapy resistance. The authors evaluated major signaling axes, discussed the limitations of chemokine-targeted monotherapy, and explored recent advances in single-cell and spatial transcriptomic technologies for characterizing compartment-specific chemokine programs. Finally, the review assessed emerging combination therapeutic strategies involving chemokine blockade.

CC chemokines are pivotal regulators of EOC progression, linking immune-cell trafficking with tumor-cell plasticity, metabolic adaptation, angiogenesis, and therapy resistance. The review identified several major signaling axes: > The CCL2-CCR2 axis is primarily associated with monocyte recruitment and myeloid-dominant immunosuppression within the TME. The CCL5-CCR5 axis is linked to stromal immune regulation and the promotion of cancer stem-like phenotypes, contributing to tumor aggressiveness and recurrence. Additional pathways, including CCL18, CCL20-CCR6, CCL22-CCR4, and CCL1-CCR8, contribute significantly to T-regulatory cell recruitment, further enhancing immune suppression and mediating hypoxia-associated responses. The review highlighted that chemokine-targeted monotherapy has shown limited efficacy due to signaling redundancy, compensatory pathways, spatial heterogeneity, and insufficient biomarker-guided patient selection. However, advances in single-cell and spatial transcriptomics are improving the characterization of these complex chemokine programs.