The enigmatic role of tumor dormancy cells in gynecologic cancers

Gynecologic cancers (GCs), including ovarian, cervical, and endometrial cancers, represent a substantial global health burden, characterized by high rates of recurrence, therapeutic resistance, and metastatic dissemination. Tumor dormancy-a state in which disseminated tumor cells (DTCs) persist in a non-proliferative, quiescent phase, thereby evading conventional therapies and immune surveillance-constitutes a critical yet often underestimated driver of these clinical challenges. This comprehensive review systematically integrates the multifaceted roles and current research landscape of dormant tumor cells in gynecologic malignancies. The core innovation lies in a three-level analytical framework that examines dormancy through intrinsic molecular switches, extrinsic microenvironmental remodeling, and cross-cancer type comparisons. Specifically, the mechanisms governing dormancy initiation, maintenance, and reactivation are delineated for cervical, ovarian, and endometrial cancers. Several key conclusions emerge from this synthesis. Common regulatory hubs across gynecologic cancers include hypoxic conditions, cell-cycle regulators such as the DREAM complex, stemness-associated pathways exemplified by the HIF-1α/PLD2 axis, and stromal cell interactions, notably cancer-associated fibroblast-extracellular matrix crosstalk. Dormant cells further orchestrate sophisticated immune evasion strategies, including downregulation of major histocompatibility complex class I and upregulation of immune checkpoint molecules, thereby establishing a reservoir of drug-tolerant persister cells that drive post-treatment relapse and acquired resistance. Notably, substantial heterogeneity exists across different gynecologic cancer types: ovarian cancer engages the most diverse repertoire of dormancy-related pathways, while uterine sarcoma remains a conspicuous research gap. Collectively, this review establishes the dormant tumor cell reservoir as a promising therapeutic target to prevent recurrence and overcome therapy resistance. Specific actionable targets-including Dyrk1A, PLD2, LATS1/2, and Egfl6-are proposed, providing a theoretical foundation for the development of novel diagnostic tools and therapeutic strategies aimed at improving long-term outcomes for patients with gynecologic malignancies.