ABSTRACT Pro‐apoptotic peptides have emerged as promising candidates in cancer therapeutics due to their ability to induce apoptosis in cancer cells while preferentially sparing normal tissues. By modulating intrinsic and extrinsic apoptotic pathways, these peptides offer a strategy to overcome drug resistance, a common challenge in conventional cancer treatments. Despite their potential, clinical translation is hindered by proteolytic instability, suboptimal delivery, and limited tumor specificity. Advances in peptide engineering, chemical modifications, and nanotechnology‐based delivery systems have significantly enhanced their stability, bioavailability, and targeting capabilities. Additionally, developing tumor‐penetrating peptides and stimuli‐responsive delivery platforms has further improved therapeutic precision. Combination therapies incorporating pro‐apoptotic peptides with chemotherapy, radiotherapy, or immunotherapy have demonstrated synergistic effects, enhancing efficacy and minimizing side effects. Preclinical studies and clinical trials involving compounds like plitidepsin, PEP‐010, GO‐203‐2C, and CIGB‐300 underscore the promise of these therapies, though further research is necessary to address current limitations. Overcoming delivery challenges, refining tumor‐specific targeting, and expanding combination strategies will be essential for maximizing their therapeutic potential. This review highlights current advancements in pro‐apoptotic peptide‐based cancer therapies, including mechanisms of action, design strategies, and delivery systems. Moreover, we discuss challenges in clinical translation and explore future directions for optimizing their therapeutic potential.
González-Cruz et al. (Mon,) studied this question.