Mechanistic Insights into Targeting the Ovarian Cancer Stem Cell Microenvironment: A Review of Therapeutic Strategies

Ovarian cancer remains the most lethal gynecologic malignancy, characterized by a poor prognosis that is mainly attributable to frequent disease recurrence and the development of chemoresistance. Central to its aggressive phenotype is the population of ovarian cancer stem cells (OCSCs), which exhibit self-renewal capacity, tumor-initiating potential, and remarkable adaptive abilities. The tumor microenvironment (TME) critically sustains these properties by providing a protective niche that maintains the stemness of OCSCs and promotes malignant behaviors. The TME comprises diverse cellular and molecular components, including immune cells, cancer-associated fibroblasts, the extracellular matrix, and soluble factors. These elements interact with OCSCs through intricate signaling networks, enhancing stem-like properties, facilitating immune evasion, and conferring resistance to conventional chemotherapy. Consequently, targeting the TME has emerged as a promising therapeutic strategy to disrupt these supportive interactions and effectively eliminate OCSCs. In this review, we systematically summarize the mechanisms by which key TME components regulate the maintenance of OCSCs' stemness, metastasis, and chemoresistance. Additionally, we highlight recent advances in therapeutic strategies targeting the microenvironment of OCSCs and discuss their efficacy, potential clinical applications, and associated translational challenges. This work aims to establish a comprehensive theoretical framework for developing novel targeted therapies that can effectively eradicate OCSCs, reverse chemoresistance, and ultimately improve clinical outcomes in patients with ovarian cancer.