Photothermal-triggered non-apoptotic regulated cell death-related pathway regulation boosts systemic antitumor immunity.

Overcoming tumor cell resistance to apoptosis and immunosuppression remains a formidable challenge in tumor immunotherapy. There is a critical need to explore alternative cell death pathways to remodel the immunosuppressive tumor microenvironment (ITME), ultimately improving therapeutic efficacy. Emerging non-apoptotic regulated cell death (RCD) modalities, including ferroptosis, pyroptosis, and immunogenic cell death (ICD), have been recognized as promising strategies for tumor immunotherapy. Mild photothermal therapy (mPTT) can reshape the ITME to trigger antitumor immunity, but its clinical use is blocked by tumor cell thermotolerance. To address this, we developed a synergistic immuno-photothermal therapy within the framework of non-apoptotic RCD, aiming to modulate the ITME. It shows remarkable capabilities in catalyzing ROS generation. Under near-infrared (NIR) irradiation, ROS production was further enhanced, leading to increased lipid peroxidation (LPO) accumulation and glutathione (GSH) depletion, collectively triggering ferroptosis. Notably, heat shock proteins (HSPs) are suppressed during ferroptosis, which further amplifies the potency of mPTT to overcome the thermotolerance hurdle presented by tumor cells. Moreover, this synergistic effect activated the Caspase-1/GSDMD-dependent pathway, consequently inducing pyroptosis. The interplay between pyroptosis and ferroptosis amplified the ICD response, resulting in the release of damage-associated molecular patterns and contributing to the remodeling of the ITME. RNA sequencing also corroborated the system's involvement in pivotal gene alterations related to ferroptosis and pyroptosis. Overall, this work is expected not only to overcome tumor cell thermotolerance during mPTT but also to address long-standing challenges in tumor treatment by extensively activating non-apoptotic RCD modalities and remodeling the ITME.