As one of the main tumor-infiltrating immune cell types, tumor-associated macrophages (TAMs) determine the efficacy of immunotherapy. However, limited knowledge about their phenotypically and functionally heterogeneous nature restricts their application in tumor immunotherapy. In this study, we identified a subpopulation of CD146⁺ TAMs that exerted antitumor activity in both human samples and animal models. CD146 expression in TAMs was negatively controlled by STAT3 signaling. Reducing this population of TAMs promoted tumor development by facilitating myeloid-derived suppressor cell recruitment via activation of JNK signaling. Interestingly, CD146 was involved in the NLRP3 inflammasome-mediated activation of macrophages in the tumor microenvironment, partially by inhibiting transmembrane protein 176B (TMEM176B), an immunoregulatory cation channel. Treatment with a TMEM176B inhibitor enhanced the antitumor activity of CD146⁺ TAMs. These data reveal a crucial antitumor role of CD146⁺ TAMs and highlight the promising immunotherapeutic approach of inhibiting CD146 and TMEM176B.

作为主要的肿瘤浸润免疫细胞类型之一，肿瘤相关巨噬细胞（TAM）决定着免疫治疗的疗效。然而，对其表型和功能异质性的了解有限，限制了它们在肿瘤免疫治疗中的应用。在这项研究中，我们鉴定了 CD146 ⁺ TAM 的一个亚群，它们在人类样本和动物模型中均发挥抗肿瘤活性。TAM 中的 CD146 表达受到 STAT3 信号传导的负控制。减少 TAM 数量可通过激活 JNK 信号传导促进骨髓源性抑制细胞的募集，从而促进肿瘤的发展。有趣的是，CD146 参与了肿瘤微环境中 NLRP3 炎性体介导的巨噬细胞激活，部分是通过抑制跨膜蛋白 176B (TMEM176B)（一种免疫调节阳离子通道）来实现的。TMEM176B 抑制剂治疗增强了 CD146 ⁺ TAM 的抗肿瘤活性。^{这些数据揭示了 CD146 +} TAM的重要抗肿瘤作用，并强调了抑制 CD146 和 TMEM176B 的有前途的免疫治疗方法。