Metastasis is the primary cause of cancer death. The inflammatory tumor microenvironment contributes to metastasis, for instance, by recruiting blood and lymph vessels. Among tumor-infiltrating immune cells, tumor-associated macrophages (TAMs) take a center stage in promoting both tumor angiogenesis and metastatic spread. We found that genetic deletion of the S1P receptor 1 (S1pr1) alone in CD11b^hi CD206⁺ TAMs infiltrating mouse breast tumors prevents pulmonary metastasis and tumor lymphangiogenesis. Reduced lymphangiogenesis was also observed in the nonrelated methylcholanthrene-induced fibrosarcoma model. Transcriptome analysis of isolated TAMs from both entities revealed reduced expression of the inflammasome component Nlrp3 in S1PR1-deficient TAMs. Macrophage-dependent lymphangiogenesis in vitro was triggered upon inflammasome activation and required both S1PR1 signaling and IL-1β production. Finally, NLRP3 expression in tumor-infiltrating macrophages correlated with survival, lymph node invasion, and metastasis of mammary carcinoma patients. Conceptually, our study indicates an unappreciated role of the NLRP3 inflammasome in promoting metastasis via the lymphatics downstream of S1PR1 signaling in macrophages.

转移是癌症死亡的主要原因。炎性肿瘤微环境例如通过募集血液和淋巴管而有助于转移。在肿瘤浸润的免疫细胞中，肿瘤相关的巨噬细胞（TAM）在促进肿瘤血管生成和转移扩散中处于中心阶段。我们发现，在浸润小鼠乳腺肿瘤的CD11b ^hi CD206 ⁺ TAM中，单独的S1P受体1（S1pr1）的基因缺失可防止肺转移和肿瘤淋巴管生成。在无关的甲基胆甾醇诱导的纤维肉瘤模型中也观察到淋巴管生成减少。从两个实体分离的TAM的转录组分析显示，炎性体成分Nlrp3的表达降低在S1PR1缺陷TAM中。炎性体激活后触发了体外巨噬细胞依赖性淋巴管生成，并且需要S1PR1信号传导和IL-1β产生。最后，NLRP3在浸润肿瘤的巨噬细胞中的表达与乳腺癌患者的生存，淋巴结浸润和转移有关。从概念上讲，我们的研究表明NLRP3炎性小体在通过巨噬细胞中S1PR1信号下游的淋巴管促进转移中的作用不明显。