Current Perspectives on Radiosensitizers in Cancer Radiotherapy

Objective: This review analyzes the multifactorial mechanisms of tumor radioresistance and evaluates the current landscape of innovative strategies to overcome this limitation, thereby improving the efficacy of radiotherapy. Methods: We evaluated the key molecular and cellular drivers contributing to radioresistance. A comprehensive evaluation of contemporary radiosensitization strategies was then undertaken, with particular focus on nanomaterials (the predominant class discussed) while also covering nanomaterials, natural bioactive compounds, targeted molecular inhibitors, immunomodulators, and nucleic acid therapies. Each class of agents was subjected to a critical analysis spanning from mechanistic insights and supportive preclinical data to progress in clinical translation. Findings from foundational in vitro research, in vivo models, and preliminary clinical studies were consolidated to form a cohesive perspective. Results: Tumor radioresistance is mediated by dynamic interactions between intrinsic cellular properties and the tumor microenvironment. Recent strategies have demonstrated potential through physical dose enhancement, multi‑target modulation, precise interference with DNA damage repair and cell‑cycle regulation, and combinatorial immunoradiotherapy. These approaches collectively enable selective tumor radiosensitization while modulating key resistance pathways. Conclusion: Despite considerable preclinical promise, clinical adoption faces challenges including biological heterogeneity, suboptimal agent delivery, normal tissue toxicity, and a lack of validated predictive biomarkers. Future advances will rely on the development of intelligent multifunctional platforms, biomarker‑guided patient stratification, and rationally designed combination therapies to achieve durable therapeutic gains. Keywords: radiotherapy, radioresistance, radiosensitivity, strategy, radiosensitizers