Cellular senescence and tumor dormancy at the crossroads of therapy resistance, metastasis and cancer stemness

Senescence is irreversible cell cycle arrest that results from therapy-induced stress such as DNA damage. It was initially thought to be a tumor-suppressive mechanism, but now getting attention to contribute to tumor progression and therapy resistance through the senescence-associated secretory phenotype (SASP). Remodeling the tumor microenvironment (TME), SASP can establish conditions conducive to tumor progression. In addition, senescence is being acknowledged increasingly as a crucial factor in inducing tumor dormancy, a state of reversible quiescence that allows cancer cells to evade therapeutic clearance and survive in protective niches. Eventually, both senescence and tumor dormancy significantly contribute to the maintenance of cancer stem cells (CSCs), enhancing their plasticity and tumor-initiating potential. Moreover, SASP can promote aggressive disease state in cancer cells, driving epithelial-to-mesenchymal transition (EMT) and metastasis. On the other hand, dormant cancer cells can act as a reservoir, serving as seeds for metastatic spread which reactivate to develop the tumor at secondary sites. Understanding senescence and tumor dormancy mechanisms holds promise for overcoming therapy resistance, cancer stemness and metastasis. Therapeutic strategies targeting cancer cell senescence and tumor dormancy include senolytics, senomorphics, dormancy-disrupting agents, and immunotherapies. Future preclinical and clinical research should prioritize integration of senescence- and dormancy-targeting agents with conventional treatments to achieve durable cancer control.