Apoptosis signaling and cancer targeted therapy: from bench to bespoke

Apoptosis is a highly regulated, programmed cell death process that serves as a fundamental safeguard against malignant transformation and tumor progression, while also acting as a critical determinant of therapeutic response. This orchestrated process is governed by both intrinsic and extrinsic signaling cascades, involving core molecular regulators including the p53 tumor suppressor, BCL-2 family proteins, caspases, inhibitor of apoptosis proteins (IAPs), and mitochondrial function. In cancer, these pathways are frequently compromised by genetic mutations or epigenetic dysregulation, allowing tumor cells to evade apoptosis and develop drug resistance. Recent advances in molecular oncology have clarified these mechanisms, paving the way for targeted approaches to restore apoptotic competence. Therapeutic strategies such as BH3 mimetics, second mitochondria-derived activator of caspases (SMAC) mimetics, p53 reactivators, caspase activators, and death receptor agonists are under preclinical and clinical evaluation, although their levels of clinical evidence are not yet uniform. Combining apoptosis-targeting agents with conventional therapies also holds promise for precision treatment. Furthermore, emerging platforms such as RNA interference (RNAi), messenger RNA (mRNA) therapy, and genome editing offer new opportunities to modulate apoptotic signaling. In this review, we summarize the molecular mechanisms of apoptosis in cancer, discuss targeted therapeutic strategies according to their signaling pathways and developmental stages, and outline future directions for apoptosis-based cancer therapy.