Cellular senescence in ovarian cancer: a proposed geroncogenic shift linking aging, plasticity, and therapy resistance

Ovarian cancer develops within a biological environment that changes substantially with age. Beyond chronological aging, progressive alterations in genome maintenance, telomere integrity, epigenetic regulation, mitochondrial function, metabolism, inflammation, and immune surveillance can reshape the cellular and tissue context in which tumor evolution occurs. Cellular senescence represents a critical point of convergence within this process. Although senescence can restrict the proliferation of damaged or oncogenically stressed cells, persistent senescent cells remain metabolically active and can alter their surroundings through the senescence-associated secretory phenotype (SASP). Here, we propose the concept of a geroncogenic shift to describe how age-associated changes in tissue homeostasis may create stress-response states that are subsequently exploited by malignant and stromal cells. We distinguish two named, complementary components of the framework: systemic decline, referring to the progressive deterioration of cellular and tissue homeostasis during aging, and pathway-specific hijacking, referring to the selective co-option of altered stress-response pathways under oncogenic or therapeutic pressure. Cellular senescence provides a functional interface between these processes because the same stress responses that constrain damaged cells can, when persistent or incompletely resolved, contribute to tumor adaptation. In ovarian cancer, senescence is not a uniform cellular endpoint. Its consequences vary according to the initiating stress, cellular compartment, molecular program, duration, and capacity for recovery or escape. Tumor-cell senescence may suppress proliferation yet also be associated with stem-like adaptation and therapeutic persistence. Senescence-associated changes in fibroblasts and other stromal populations can reshape inflammatory signaling and treatment response, while polyploid and senescence-like states illustrate the extent of cellular plasticity that can exist after therapeutic stress. The SASP further extends the effects of senescence beyond individual cells by influencing neighboring tumor and stromal populations, extracellular-matrix remodeling, inflammation, and dissemination. This perspective has important therapeutic implications. Rather than treating senescence as either a uniformly protective or pathogenic state, therapeutic strategies should distinguish between senescent-cell elimination, SASP modulation, metabolic vulnerabilities, and prevention of senescence escape. We propose that understanding the cellular context and temporal dynamics of senescence will be essential for determining when senescence should be induced, maintained, modulated, or eliminated in ovarian cancer. Most therapeutic evidence for senescence-directed strategies remains preclinical, and clinical translation will require cell-type-specific biomarkers and optimized treatment timing. The geroncogenic shift framework therefore provides a conceptual basis for linking aging biology with tumor evolution and for developing more selective approaches to senescence-directed therapy.