The Double-Edged Sword of Therapy-Induced Senescence in Cancer Treatment
The dominant forms of cancer therapy, chemotherapy and radiotherapy, induce senescence in cancer cells they cannot kill, as well as in non-cancerous cells exposed to the treatment. Entering the senescent state is a response to a high level of stress and damage that isn't sufficient to kill the cell. A senescent cancer cell no longer replicates, and so promoting senescence continues to be seen as an acceptable goal to hinder the cancer. Cancer survivors are left with a high burden of cellular senescence, however, and as a result exhibit accelerated aging: higher mortality, higher risk of age-related conditions, including other cancers. Senotherapeutics such as senolytic drugs to selectively destroy senescent cells offer the possibility of dramatically reducing the consequences of an increased burden senescence induced by cancer therapies.
Therapy-induced senescence (TIS) has emerged as a central biological response to anticancer therapies, extending beyond tumor suppression to influence long-term tissue homeostasis, cardiovascular (CV) remodeling, and accelerated biological aging. Chemotherapy, radiotherapy, targeted therapies, and emerging immune-activating treatments can induce senescence not only in malignant cells, where it may initially contribute to tumor growth arrest and immune-mediated clearance, but also in non-malignant CV tissues. Persistent accumulation of senescent cells and sustained release of the senescence-associated secretory phenotype (SASP) represent a double-edged sword that may promote chronic inflammation and endothelial dysfunction while contributing to the exacerbation of multifactorial CV outcomes, including myocardial fibrosis, vascular stiffness, and progressive CV dysfunction.
Increasing evidence suggests that TIS-associated mechanisms - including persistent DNA damage response activation, p53/p21- and p16INK4a-mediated cell-cycle arrest, NF-κB-driven inflammatory signaling, mitochondrial dysfunction, oxidative stress, and metabolic rewiring - overlap with pathways involved in CV toxicity and systemic tissue remodeling. Through chronic inflammatory and immune-vascular crosstalk, TIS may contribute to a broader phenotype of inflammaging and therapy-associated premature biological aging.
Emerging senescence-targeting strategies, including senolytic and senomorphic therapies, represent promising approaches to mitigate long-term CV injury while preserving antitumor efficacy, although their clinical benefit and safety remain to be fully established. This review summarizes current knowledge regarding the dual and systemic role of TIS in cancer and CV disease, considering TIS as a candidate, non-exclusive mediator acting alongside direct therapy-related injury, and discusses its translational implications for integrated precision cardio-oncology strategies.