Phototherapy-responsive nanoplatform with hydrogel delivery potentiates immunotherapy and inhibits lung metastasis in osteosarcoma via synergistic glycolysis inhibition and vascular normalization.

The immunosuppressive tumor microenvironment (ITME)-marked by acidosis and hypoxia-persists as a critical barrier to cancer immunotherapy, especially for osteosarcoma. Herein, an injectable pH-responsive nanocomposite hydrogel (OP@NPs) is presented to overcome this challenge via coordinated metabolic modulation, vascular normalization, and immune reprogramming. This platform co-delivers a novel lactate metabolism inhibitor (D780, a derivative conjugated by IR780 and diclofenac), Zn²⁺, and the anti-angiogenic agent nintedanib (NIB). D780 inhibits key glycolytic enzymes to reduce lactate production, while exerting photothermal/photodynamic effects that directly ablate tumors and mitigate hypoxia. Through metal coordination, Zn²⁺ assembles NIB and D780 into NPs. It also blocks GLUT1, boosting D780's inhibition of glycolysis. NIB can restore abnormal vascular structure, thereby alleviating oxidative hypoxia and blocking epithelial-mesenchymal transition. In murine osteosarcoma models, the combined therapy centered on OP@NPs remodelled the tumor immune microenvironment (TME). This transformation led to an accumulation of cytotoxic T cells, dendritic cells and M1 macrophages. The treatment achieved favorable outcomes in inhibiting primary tumor growth and pulmonary metastases. Overall, this work presents a localized targeting strategy to regulate key signaling pathways in osteosarcoma.