Multiple-pathway cGAS-STING activation with enhanced mild photothermal therapy through glycolysis regulation for boosting gastric cancer immunotherapy.

Chemotherapy and photothermal therapy (PTT) have made prominent progress in the treatment of gastric cancer. However, the poor targeting of chemotherapeutic drugs and the thermotolerance or collateral damage induced by PTT lead to suboptimal therapeutic outcomes. To address these issues, we developed a mild PTT (mPTT) nanoparticle based on mesoporous polydopamine (MPDA), loaded with oxaliplatin (OXP) and manganese dioxide (MnO), and coated with tumor cell membranes to enhance the targeting capability. On one hand, this nanoparticle disrupts glycolysis by inhibiting hypoxia-inducible factor (HIF), while suppressing heat shock proteins (HSP) to mitigate tumor "thermotolerance". On the other hand, the reactive oxygen species (ROS) generated by the MnO-mediated Fenton-like reaction, OXP, and mPTT also induce immunogenic cell death (ICD) to boost adaptive immunity, as well as activate the cGAS-STING pathway through tumor DNA damage to reinforce innate immunity. The activation of both adaptive and innate immune responses triggers a potent antitumor immune reaction, which, combined with chemotherapy and enhanced mPTT, significantly suppresses tumor growth, metastasis and recurrence. This strategy not only enhances the targeting of chemotherapeutic drugs but also provides new possibilities for expanding the field of immunotherapy in gastric cancer by regulating tumor metabolism and enhancing mPTT.