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The HRR genes\n                    <jats:italic>BRCA1<\/jats:italic>\n                    \/\n                    <jats:italic>2<\/jats:italic>\n                    are key regulators of DNA repair, yet their impact on the tumor microenvironment (TME) in lung adenocarcinoma (LUAD) remains unclear. Using single-cell sequencing and multi-omics data, we characterized\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    mutation-associated transcriptional programs, immune cell composition, and functional alterations in T cells, investigating the molecular and immune architecture of BRCA-mutant LUAD patients.\n                    <jats:italic>BRCA1<\/jats:italic>\n                    \/\n                    <jats:italic>2<\/jats:italic>\n                    mutations were associated with increased genomic instability and poor prognosis in LUAD patients, but predicted better clinical outcomes following immune checkpoint blockade (ICB) treatment.\n                    <jats:italic>BRCA1<\/jats:italic>\n                    mutations correlated with an upregulated type I IFN\/IFN-\u03b3 signature and CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell activation.\n                    <jats:italic>BRCA2<\/jats:italic>\n                    mutations were associated with alveolar\/stress\/inflammatory responses and enhanced MHC-II antigen presentation, linked to CD4\n                    <jats:sup>+<\/jats:sup>\n                    T cell differentiation. Both alterations coincided with reduced CD28 co-stimulation and CTL activity, hinting at immune evasion. We identified two tissue-resident memory T cell (Trm) subsets as predictors of clinical outcomes and ICB response.\n                    <jats:italic>BRCA1<\/jats:italic>\n                    mutations were associated with CD8\n                    <jats:sup>+<\/jats:sup>\n                    Trm expansion, whereas\n                    <jats:italic>BRCA2<\/jats:italic>\n                    mutations were linked to tumor CD4\n                    <jats:sup>+<\/jats:sup>\n                    Trm expansion and peripheral T\/NK cell cytotoxicity. Furthermore, a cancer-promoting program activated by\n                    <jats:italic>BRCA1<\/jats:italic>\n                    mutation was vulnerable to histone deacetylase inhibitors, which inhibited LUAD tumor growth. This study provides a preliminary characterization of the BRCA-mutant TME in LUAD patients, revealing distinct transcriptional and immune patterns that highlight differences in\n                    <jats:italic>BRCA1\/2<\/jats:italic>\n                    -associated molecular architecture and offer a framework for improving therapy efficacy in LUAD.\n                  <\/jats:p>","DOI":"10.7554\/elife.110662","type":"journal-article","created":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T15:30:15Z","timestamp":1773243015000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.110662","source":"Crossref","is-referenced-by-count":1,"title":["Molecular architecture of the tumor microenvironment caused by BRCA1 and BRCA2 somatic mutations in human lung 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