MAP3K1 mutations confer tumor immune heterogeneity in hormone receptor-positive HER2-negative breast cancer

Hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, the most common type of breast cancer, is facing challenges such as endocrine therapy resistance and distant relapse. Immunotherapy has shown progress in treating triple-negative breast cancer, but immunological research on HR+/HER2- breast cancer is still in its early stages. Here, we performed a multi-omics analysis of a large cohort of HR+/HER2- breast cancer patients (n = 351) and revealed that HR+/HER2- breast cancer possessed a highly heterogeneous tumor immune microenvironment. Notably, the immunological heterogeneity of HR+/HER2- breast cancer was related to MAP3K1 mutation and we validated experimentally that MAP3K1 mutation could attenuate CD8+ T cell-mediated antitumor immunity. Mechanistically, MAP3K1 mutation suppressed MHC-I-mediated tumor antigen presentation through promoting the degradation of antigen peptide transporter 1/2 (TAP1/2) mRNAs, thereby driving tumor immune escape. In preclinical models, the postbiotics tyramine could reverse the MAP3K1 mutation-induced MHC-I reduction, thereby augmenting the efficacy of immunotherapy. Overall design: 67NR mouse breast cancer cell lines were knocked out for Map3k1 expression. The knocked-out cell lines were then overexpressed with either Map3k1-WT (WT) or Map3k1-Mut (Mut: 1-1222 aa), and then orthotopically injected into BALB/c mice (randomly assigned). When the tumor volume reached 1000 mm3, mice were euthanized using the carbon dioxide method, and tumors were dissected and sent for RNA sequencing.