Macrophages serve as the first line of communication between tumors and the rest of the immune system, and understanding the interplay between macrophage and tumor cells is essential for developing novel macrophage-based strategy against tumor. Here, we show that deletion of legumain in macrophages activates senescence of tumor cells. Macrophage derived IL-1β mediates the pro-senescent effect of Lgmn-/- macrophages since blockage of IL-1β reverses the senescence phenotype in both a coculture model of macrophage and tumor cells and an orthotopic mouse model of breast cancer. Sustained activation of JAK1/STAT1 signaling and increased iNOS were found in the tumor cell-cocultured Lgmn-/- macrophages, which were necessary for IL-1β expression and secretion. Applying a specific STAT1 agonist mimics the inductive effect of legumain deletion on IL-1β expression in macrophages, and the effect can be blocked via inhibition of iNOS. Legumain and integrin αvβ3 interact to prevent STAT1 signaling in macrophages, and blockage of integrin αvβ3 stimulates STAT1 activation. Therapeutically, transplantation of bone marrow from Lgmn-/- mice suppresses the malignant growth of tumor by upregulating tumor cell senescence. Therefore, our finding highlights legumain in macrophages as a potential therapeutic target for tumors.

中文翻译：

---

缺乏豆蔻蛋白酶的巨噬细胞通过维持JAK1 / STAT1激活来促进肿瘤细胞的衰老。

巨噬细胞是肿瘤与免疫系统其他部分之间的第一线交流，了解巨噬细胞与肿瘤细胞之间的相互作用对于开发新的基于巨噬细胞的抗肿瘤策略至关重要。在这里，我们表明巨噬细胞中豆蔻蛋白酶的缺失激活了肿瘤细胞的衰老。巨噬细胞衍生的IL-1β介导Lgmn-/-巨噬细胞的促衰老作用，因为在巨噬细胞和肿瘤细胞的共培养模型和乳腺癌的原位小鼠模型中，IL-1β的阻断都会逆转衰老表型。在肿瘤细胞共培养的Lgmn-/-巨噬细胞中发现了JAK1 / STAT1信号的持续激活和iNOS的增加，这对于IL-1β的表达和分泌是必需的。应用特定的STAT1激动剂可模拟豆蔻因缺失对巨噬细胞IL-1β表达的诱导作用，并且可以通过抑制iNOS来阻断这种作用。豆蔻因和整联蛋白αvβ3相互作用以防止巨噬细胞中的STAT1信号传导，而整联蛋白αvβ3的阻滞刺激了STAT1的激活。在治疗上，从Lgmn-/-小鼠骨髓移植可通过上调肿瘤细胞的衰老来抑制肿瘤的恶性生长。因此，我们的发现突出了巨噬细胞中的豆科菌素作为肿瘤的潜在治疗靶标。Lgmn-/-小鼠骨髓移植可通过上调肿瘤细胞衰老来抑制肿瘤的恶性生长。因此，我们的发现突出了巨噬细胞中的豆科菌素作为肿瘤的潜在治疗靶标。Lgmn-/-小鼠骨髓移植可通过上调肿瘤细胞衰老来抑制肿瘤的恶性生长。因此，我们的发现突出了巨噬细胞中的豆科菌素作为肿瘤的潜在治疗靶标。