Modulation of Tumor Microenvironments with Phenolic ROS Nanoscavengers for Cancer Immunotherapy

Tumor immunotherapy remains constrained by the immunosuppressive tumor microenvironments (TME), where elevated reactive oxygen species (ROS) impair cytotoxic T lymphocyte function and promote immune tolerance. Herein, we report the synthesis of porous allomelanin nanoparticles (AMNPs) loaded with TLR7/8 agonist of imidazoquinoline (IMDQ) for synergistic ROS scavenging and immunoactivation. The IMDQ-loaded AMNPs (IAMNPs) effectively scavenged ROS, attenuated NF-κB-mediated inflammation, and promoted dendritic cell maturation in vitro. In murine melanoma models, IAMNPs could reshape the immunosuppressive TME by decreasing regulatory T cells, myeloid-derived suppressor cells, and M2-type tumor-associated macrophages, while enhancing infiltration and activation of CD8+ and CD4+ T cells. When combined with anti-PD-L1, IAMNPs significantly suppressed primary tumor growth and pulmonary metastasis, which improved survival rates of mice. This study demonstrates a potent nanoplatform that concurrently modulates oxidative stress and innate immunity to potentiate checkpoint blockade therapy, providing a promising combinatorial strategy for cancer immunotherapy.