BRIP1-mediated RINT1 acetylation and NF-κB activation promote DNA repair and immunosuppressive microenvironment in...

Immune evasion remains a major obstacle to effective therapy in lung adenocarcinoma (LUAD), and accumulating evidence suggests that DNA damage repair programs actively shape tumor immunity. Here, we identify the Fanconi anemia pathway helicase BRIP1 as a critical coordinator of DNA repair competence and innate immune suppression in LUAD. BRIP1 is significantly upregulated in tumor tissues and correlates with advanced clinical stage and poor prognosis. Functional assays demonstrate that BRIP1 promotes LUAD cell proliferation, invasion, epithelial-mesenchymal transition, and homologous recombination (HR) repair capacity. Mechanistically, BRIP1 drives tumor progression through two interconnected pathways. First, BRIP1 associates with the histone variant macroH2A1 to enhance acetylation of RINT1 at lysine 728, thereby strengthening RINT1-RAD50 interaction, facilitating MRE11-RAD50-NBS1 complex assembly, and augmenting HR-mediated DNA repair. Enhanced repair efficiency limits cytosolic DNA accumulation and suppresses cGAS-STING-dependent innate immune activation. Second, BRIP1 interacts with the RNA demethylase ALKBH5, leading to activation of NF-κB signaling, upregulation of PD-L1, and promotion of metastatic potential. Spatial transcriptomics, single-cell RNA sequencing, and multiplex immunohistochemistry reveal that BRIP1-high tumors exhibit an immune-cold microenvironment characterized by regulatory T-cell enrichment, cytotoxic T-cell exclusion, and impaired immune communication. In vivo, BRIP1 overexpression accelerates tumor growth and metastasis while conferring resistance to PD-L1 blockade, which is effectively reversed by combining anti-PD-L1 therapy with STING activation. Collectively, our findings establish BRIP1 as a molecular link between DNA repair proficiency and immune suppression in LUAD, highlighting BRIP1-associated pathways as actionable targets for rational combination immunotherapy.