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

Abstract

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.