Photothermal targeting of lactate metabolism reverses radioresistance via disrupting the immunosuppressive barrier.

Radiotherapy (RT) is frequently compromised by radioresistance and insufficient immunogenicity. Multiomics analysis here identifies a significant association between glycolysis and DNA damage repair, linking them to RT resistance and poor patient survival. To address this, we develop a mild thermia-guided radiosensitizer, GQD@PDA/Au, which reprograms glycolytic metabolism upon photothermal stimulation to inhibit lactate accumulation. Reduced lactate levels aggravate DNA damage and dsDNA breaks, thereby enhancing tumor radio-immunogenicity by activating the cGAS-STING pathway, inducing tumor ICD, and facilitating dendritic cell maturation. This work develops a clinically translatable platform that overcomes RT resistance and augments antitumor immunity via mild thermia-responsive radiosensitization.