Dual-functional catalytic photothermal immunological agent for ferroptosis induction and cGAS-STING pathway activation: Enhancing tumor immunotherapy and generating robust immune memory.

The resistance to apoptosis and immune evasion of tumor cells significantly increase the risk of cancer treatment failure. Ferroptosis has emerged as a new strategy to address apoptosis resistance in tumor therapy. However, traditional ferroptosis inducers often lead to drug resistance due to the compensatory mechanism of GPX4, while the synergistic effect of photothermal-immunotherapy can circumvent this limitation. Additionally, relying solely on innate immunotherapy may fail to effectively suppress aggressive tumors with "cold" and immunosuppressive microenvironments, thereby inducing immune escape. Here, we have meticulously developed a mild photothermal immunotherapy nanoplatform (termed Fe-Mn@GOx NPs), designed to induce non-apoptotic ferroptosis, augment cGAS-STING pathway activation and enhance innate anti-tumor immunity. This strategy directly disrupts the structure of heat shock protein (HSP) to restore the sensitivity of cancer cells and enhance antitumor immunity. Notably, Fe-Mn@GOx NPs-mediated ferroptosis induces an elevation in reactive oxygen species (ROS) levels within tumor cells. Additionally, glucose depletion itself primarily affects ATP levels. ROS-mediated oxidative damage, combined with ATP depletion-induced functional inhibition, synergistically inhibits heat shock protein (HSP) expression, thereby offering a potent approach for mild photothermal immunotherapy. More critically, the cGAS-STING pathway in macrophages is further activated by tumor-derived endogenous DNA contained within Fe-Mn@GOx NPs-induced dead cell debris, simultaneously promoting the generation of long-term immune memory T cells. The interplay between ferroptosis and the cGAS-STING pathway triggers rapid induction of systemic antitumor immunity, leading to suppression of tumor growth. The engineered nanotherapeutic platform enables a novel tumor immunotherapy strategy through specific cGAS-STING pathway activation.