A ROS-responsive injectable hydrogel orchestrating photothermal-immune synergy for osteosarcoma therapy through spatiotemporal immuno-microenvironment remodeling.

Osteosarcoma (OS) is characterized by a profoundly immunosuppressive tumor microenvironment (TME) that limits the efficacy of immunotherapy. Although photothermal therapy (PTT) can induce immunogenic cell death (ICD) and promote tumor antigen release, it is insufficient to elicit durable antitumor immunity. Here, we develop a tumor microenvironment-responsive injectable hydrogel (MP@TPH) that mechanistically integrates photothermal ablation with localized activation of innate immunity. MP@TPH co-encapsulates polydopamine nanoparticles and PDA-coated MSA-2, a stimulator of interferon genes (STING) agonist, enabling near-infrared-induced tumor ablation and reactive oxygen species (ROS)-triggered release of immune modulators. Mechanistically, PTT-induced ICD facilitates antigen liberation, while ROS-responsive delivery of MSA-2 enhances dendritic cell activation and immune priming. In a murine K7M2 osteosarcoma model, MP@TPH combined with irradiation markedly suppresses tumor growth without detectable systemic toxicity. This work establishes a TME-adaptive platform that couples photothermal therapy with spatially confined STING activation, offering a mechanistically grounded strategy to overcome immune resistance in osteosarcoma.