Tumor microenvironment-rearranging Nanoassemblies overcome angiogenesis-immunotherapy resistance to potentiate osteosarcoma treatment.

Conventional anti-angiogenic cancer therapy is frequently undermined by adaptive tumor hypoxia and the consequent establishment of an immunosuppressive microenvironment, which together drive therapeutic resistance. To overcome this limitation, we engineered a tumor-targeted nano-platform (Reg@CeO2@HA) that co-delivers low-dose regorafenib with enzymatically versatile cerium oxide nanoparticles. This system concurrently normalizes tumor vasculature, scavenges pathological reactive oxygen species, and alleviates hypoxia-collectively reprogramming the immunosuppressive tumor landscape. Mechanistically, the platform could downregulate PD-L1 expression, reduce infiltration of M2-polarized tumor-associated macrophages, and attenuate myeloid-derived suppressor cell-mediated T-cell exhaustion. Furthermore, it could induce immunogenic cell death, thereby priming a systemic anti-tumor immune response. In combination with PD-L1 blockade, Reg@CeO2@HA could elicit potent synergistic efficacy, marked by robust CD8+ T-cell infiltration and profound tumor suppression. Taken together, the present study established a novel therapeutic paradigm that concurrently addresses vascular abnormality and immune dysfunction within the TME. This integrated nano-strategy could not only overcome the key limitations of conventional anti-angiogenic therapy but also provide a versatile and potent approach to sensitize osteosarcoma and other immunologically cold solid tumors to immunotherapy.