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. Collectively, our study identified the vital biomarker driving the immunological heterogeneity of HR+/HER2- breast cancer and elucidated the underlying molecular mechanisms, which provided the promise of tyramine as a novel therapeutic strategy to enhance the efficacy of immunotherapy.

中文翻译：

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MAP3K1 突变在激素受体阳性 HER2 阴性乳腺癌中赋予肿瘤免疫异质性。


激素受体阳性 （HR+）/人表皮生长因子受体 2 阴性 （HER2-） 乳腺癌是最常见的乳腺癌类型，正面临内分泌治疗耐药和远处复发等挑战。免疫疗法在治疗三阴性乳腺癌方面已显示出进展，但对 HR+/HER2- 乳腺癌的免疫学研究仍处于早期阶段。在这里，我们对一大群 HR+/HER2- 乳腺癌患者 （n = 351） 进行了多组学分析，发现 HR+/HER2- 乳腺癌具有高度异质性的肿瘤免疫微环境。值得注意的是，HR+/HER2- 乳腺癌的免疫异质性与 MAP3K1 突变有关，我们通过实验验证 MAP3K1 突变可以减弱 CD8+ T 细胞介导的抗肿瘤免疫。从机制上讲，MAP3K1 突变通过促进抗原肽转运蛋白 1/2 （TAP1/2） mRNA 的降解来抑制 MHC-I 介导的肿瘤抗原呈递，从而驱动肿瘤免疫逃逸。在临床前模型中，后生元酪胺可以逆转 MAP3K1 突变诱导的 MHC-I 减少，从而增强免疫疗法的疗效。总的来说，我们的研究确定了驱动 HR+/HER2- 乳腺癌免疫异质性的重要生物标志物，并阐明了潜在的分子机制，这为酪胺作为增强免疫疗法疗效的新型治疗策略提供了前景。