The tumor microenvironment (TME) profoundly influences tumorigenesis, with gene expression in the breast TME capable of predicting clinical outcomes. The TME is complex and includes distinct cancer-associated fibroblast (CAF) subtypes whose contribution to tumorigenesis remains unclear. Here, we identify a subset of myofibroblast CAFs (myCAF) that are senescent (senCAF) in mouse and human breast tumors. Utilizing the MMTV-PyMT;INK-ATTAC (INK) mouse model, we found that senCAF-secreted extracellular matrix specifically limits natural killer (NK) cell cytotoxicity to promote tumor growth. Genetic or pharmacologic senCAF elimination unleashes NK cell killing, restricting tumor growth. Finally, we show that senCAFs are present in HER2+, ER+, and triple-negative breast cancer and in ductal carcinoma in situ (DCIS) where they predict tumor recurrence. Together, these findings demonstrate that senCAFs are potently tumor promoting and raise the possibility that targeting them by senolytic therapy could restrain breast cancer development. Significance: senCAFs limit NK cell-mediated killing, thereby contributing to breast cancer progression. Thus, targeting senCAFs could be a clinically viable approach to limit tumor progression.

中文翻译：

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衰老的 CAF 介导免疫抑制并推动乳腺癌进展

肿瘤微环境 (TME) 深刻影响肿瘤发生，乳腺 TME 中的基因表达能够预测临床结果。 TME 很复杂，包括不同的癌症相关成纤维细胞 (CAF) 亚型，其对肿瘤发生的贡献尚不清楚。在这里，我们鉴定了小鼠和人类乳腺肿瘤中衰老的肌成纤维细胞 CAF (myCAF) 的一个子集 (senCAF)。利用 MMTV-PyMT;INK-ATTAC (INK) 小鼠模型，我们发现 senCAF 分泌的细胞外基质特异性限制自然杀伤 (NK) 细胞的细胞毒性，从而促进肿瘤生长。遗传或药物消除 senCAF 会释放 NK 细胞杀伤作用，限制肿瘤生长。最后，我们发现 senCAF 存在于 HER2+、ER+ 和三阴性乳腺癌以及导管原位癌 (DCIS) 中，它们可以预测肿瘤复发。总之，这些发现表明 senCAF 具有强大的肿瘤促进作用，并提出了通过 senolytic 疗法靶向它们可以抑制乳腺癌发展的可能性。意义：senCAF 限制 NK 细胞介导的杀伤，从而促进乳腺癌进展。因此，靶向 senCAF 可能是限制肿瘤进展的临床可行方法。