Ferroptosis-driven anti-heat endurance augments photothermal-therapy of uveal melanoma via a multifunctional liposome.

Uveal melanoma (UM) is an intraocular malignancy in adults that is highly invasive, prone to early metastasis and carries a poor prognosis. Irradiation remains a central part of treatment for UM, but resistance to therapy often limits efficacy and contributes to persistently low overall survival. To address these challenges, we developed a folate (FA)-functionalized liposome that co-delivers the photothermal agent IR-1061 and the ferroptosis inducer RSL3 (I/R@FA-Lipo) for targeted, synergistic photothermal therapy (PTT) and ferroptosis. Upon near-infrared laser irradiation, we found that I/R@FA-Lipo generates localized hyperthermia and simultaneously catalyzes reactive oxygen species production. This triggers lipid peroxidation and glutathione depletion, robustly enhancing ferroptosis by released RSL3. Notably, ferroptosis-mediated suppression of heat shock proteins overcomes PTT-trigger thermotolerance of tumors, thereby enhancing PTT efficacy and significantly suppressed UM growth with minimal adverse effects. RNA sequencing confirmed that I/R@FA-Lipo modulates key ferroptosis-associated gene pathways to amplify the antitumor response. This work highlights a targeted nanotherapeutic strategy that integrates PTT with ferroptosis, offering a promising approach to overcome treatment resistance in UM and other refractory cancers.