A USP8-Targeting Nanoamplifier Synergizes with Radiotherapy to Remodel the Immunosuppressive Tumor Microenvironment in Lung Cancer

Radiotherapy (RT) remains a cornerstone in lung cancer treatment, but its efficacy is often limited by radioresistance and an immunosuppressive tumor microenvironment (TME). Here, we identify the deubiquitinating enzyme USP8 as a key regulator of M2-like tumor-associated macrophages (TAMs) in the irradiated TME. To exploit this finding, we developed a biomimetic nanoparticle, USP8@CPMOF, which co-delivers a USP8 inhibitor and an anti-PD-L1 nanobody-coated membrane. This nanosystem specifically targets both irradiated tumor cells and TAMs, responding to the acidic and high-glutathione TME to trigger ferroptosis and release the USP8 inhibitor. In vitro, USP8@CPMOF enhanced RT-induced apoptosis and ferroptosis, promoted dendritic cell maturation, and reprogrammed M2 macrophages toward an M1 phenotype. In vivo, it improved tumor accumulation, synergized with RT to suppress tumor growth and metastasis, and robustly remodeled the TME by increasing cytotoxic T cell infiltration and reducing immunosuppressive cells. This work presents a promising nanomedicine strategy to overcome radioresistance by simultaneously targeting tumor cells and the immunosuppressive TME.