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

Abstract

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.