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.