Prophylactic sequential drug administration potentiates cancer radiotherapy by inhibiting cholesterol deposition and...

Radiotherapy serves as a mainstream cancer therapy modality, while the adaptive resistance induced by ionizing radiation (IR) hampers the therapeutic efficacy. Among various factors underlying radioresistance, lysosomal cholesterol deposition and cellular senescence emerge with complicated interrelation, leaving unclear mechanism and inadequate solutions. Herein, we evaluate the IR-induced variations of cancer cells that result in radioresistance, guiding the development of nanomedicine (U@HC) capable of stepwise drug release to enhance radiotherapy. U@HC leverage the acidic environment and high glutathione levels in tumors to sequentially release U18666A and β-cyclodextrin. The pretreatment with U@HC inhibits the abnormal accumulation of lysosomal cholesterol in cancer cells during radiotherapy, and meanwhile reduces cellular senescence and senescence-associated secretory phenotype, thereby achieving potent radiosensitization to prolong mice survival. This study proposes a novel strategy to mitigate cellular senescence through the regulation of lysosomal cholesterol, offering a clinically promising approach to overcome radioresistance and improve the effectiveness of cancer radiotherapy.