Tumor cells escape from therapy-induced senescence: from molecular mechanisms to targeted intervention

Tumor recurrence represents a significant challenge in the field of tumor therapy, severely affecting patients' survival rates and quality of life. Even after standard treatments, many patients still experience tumor recurrence. Traditional radiotherapy, chemotherapy, and targeted therapies can induce tumor cell senescence to suppress tumor growth and dissemination. However, recent studies have shown that therapy-induced senescent tumor cells can re-enter the cell cycle, acting as a key driver of tumor recurrence. Consequently, senescent tumor cells have emerged as a pivotal focus for unraveling the mechanisms underlying tumor recurrence. This review systematically elucidates the multidimensional molecular regulatory networks through which senescent tumor cells promote tumor recurrence, encompassing key processes such as cell cycle reactivation mechanisms, epithelial-mesenchymal transition (EMT), acquisition of stemness phenotypes, formation of polyploid giant cancer cells (PGCCs), fate transition from senescence to pyroptosis, and remodeling of the immune microenvironment. Additionally, it summarizes the latest advances in targeted interventions against senescent tumor cells, including senolytics-mediated clearance of senescent cells and senomorphic modulation of the senescence-associated secretory phenotype (SASP). Furthermore, we propose that, guided by the molecular mechanisms underlying senescent tumor cell-mediated recurrence, the integration of multi-omics analyses to precisely delineate the therapeutic window, combined with artificial intelligence-driven drug screening, holds promise for developing more specific senolytic agents, thereby offering innovative strategies to improve recurrence control rates following cancer therapy.