Natural radiosensitizers in cancer therapy: Mechanisms, radioresistance modulation, and translational prospects

Cancer radiotherapy has made significant strides, yet the persistent challenge of tumor radioresistance continues to compromise therapeutic success. This obstacle stems from a multifaceted network of biological mechanisms, including enhanced DNA damage response, checkpoint dysregulation, hypoxia, metabolic reprogramming, and adaptations within the tumor microenvironment. The superior biocompatibility of phytochemicals positions them as promising candidates for combination approaches, and they have gained increasing attention as safer and mechanistically diverse radiosensitizers. Five major classes of phytochemicals, including coumarins, flavonoids, alkaloids, polyphenols, and terpenoids, are systematically reviewed. Promising radiosensitizing effects have been reported for coumarins, such as auraptene and osthole, as well as for flavonoids, including quercetin, luteolin, and apigenin. The repertoire of natural radiosensitizers is further expanded by alkaloids, such as piperlongumine and berberine, polyphenols, like curcumin and resveratrol, and terpenoids, such as thymoquinone. Despite encouraging preclinical findings, several consistent and critical limitations have been identified across the literature, including the absence of standardized efficacy metrics, heterogeneity in experimental designs, sparse in vivo validation, and unaddressed questions regarding normal cell selectivity. Consequently, clinical validation remains nascent, with only a few early-phase trials having investigated flavonoid-based formulations. By critically synthesizing current evidence and identifying translational gaps, this review provides a foundation for the future development of phytochemical radiosensitizers as viable adjuncts in multimodal cancer therapy.