BRCC3 promotes progression and immune evasion in non-small cell lung cancer through regulation of PD-L1 and B7-H3.

While elevated levels of the deubiquitinating enzyme BRCC3 have been documented in a range of cancers, its capacity to influence immune checkpoint expression or enable tumor immune evasion in non-small cell lung cancer (NSCLC) remains uncharacterized. BRCC3 expression and clinical relevance were assessed using TIMER2, UALCAN, and Kaplan-Meier Plotter databases, and validated in NSCLC tissues and cell lines. Functional impacts were evaluated through proliferation, migration, invasion, and syngeneic tumor models. CD8+ T cell cytotoxicity and cytokine secretion were measured in co-culture systems. Protein interactions and ubiquitination of PD-L1/B7-H3 were analyzed by co-immunoprecipitation and western blot. Rescue experiments with PD-L1 or B7-H3 overexpression were performed. BRCC3 upregulation correlated with advanced NSCLC, nodal spread, and worse survival. BRCC3 knockdown suppressed malignant phenotypes and tumor growth, and shifted the immune response toward a proinflammatory phenotype, accompanied by enhanced CD8 + T cell killing. Mechanistically, BRCC3 directly interacted with PD-L1 and B7-H3, enhancing their protein levels via deubiquitination. Overexpression of either PD-L1 or B7-H3 partially restored tumor growth and attenuated T cell activation induced by BRCC3 silencing. BRCC3 drives immune escape in NSCLC by deubiquitination-mediated upregulation of PD-L1 and B7-H3, thereby dampening anti-tumor immunity. Targeting BRCC3 may represent a potential therapeutic strategy to overcome resistance to current immunotherapies.