Therapy-induced senescence in breast cancer and cardiovascular disease: a double-edged biological process

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. In breast cancer (BC), 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. Importantly, these outcomes cannot be attributed to TIS alone, as direct therapy-related injury and pre-existing CV risk factors may also contribute. Increasing evidence suggests that TIS-associated mechanisms - including persistent DNA damage response activation, p53/p21- and p16^INK4a^-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 BC 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.