Cellular senescence and regulated cell death in cancer: mechanisms, cross-regulatory networks and therapeutic implications

Abstract

Cellular senescence and regulated cell death represent two fundamental but intricately connected biological programs that govern tumor cell fate. Cellular senescence can suppress tumor growth by inducing stable cell-cycle arrest and promoting immune clearance, but persistent senescent cells may also drive tumor progression through the senescence-associated secretory phenotype (SASP). Concurrently, multiple modalities of regulated cell death—including apoptosis, ferroptosis, cuproptosis, necroptosis, pyroptosis, parthanatos, and autophagy-dependent cell death—have emerged as critical determinants of therapeutic response. The crosstalk between senescence and cell death is orchestrated by key molecular hubs including p53, mitochondria, autophagy machinery, and epigenetic regulators. In this review, we summarize the hallmarks and classification of cellular senescence in cancer, outline major cell death modalities, discuss the cross-regulatory networks linking senescence and death, and highlight emerging therapeutic strategies that target these interconnected processes for cancer treatment.