IL-33是一种危险信号，与其受体ST2L结合以促进肿瘤进展。这项研究确定了巨噬细胞中 IL-33/ST2L 正反馈环路和 ST2L 膜表达的运输，这有助于肺肿瘤的进展。从机制上讲，IL-33 通过激活 NF-κB（与 ST2L 基因的启动子区域结合）诱导 ST2L 上调。此外，Rab37（一种参与膜运输的小型 GTP 酶）介导 ST2L 运输至 M2 巨噬细胞的质膜。该 IL-33/NF-κB/ST2L/Rab37 轴促进正反馈环，从而增强 M2 巨噬细胞中的 ST2L 表达和膜运输。值得注意的是，针对 IL-33 或 ST2L 的中和抗体可阻断 NF-κB 活性，抑制 M2 巨噬细胞极化，并在体外/体内与顺铂治疗相结合时协同抑制肿瘤生长。临床上，Rab37 /ST2L /CD206肿瘤浸润M2巨噬细胞与化疗反应不佳的晚期肺癌患者相关。这些发现揭示了一种正反馈机制，并为癌症的 IL-33/ST2L 靶向治疗提供了基础。© 2024。作者。

IL-33 is a danger signal that binds to its receptor ST2L to promote tumor progression. This study identifies the IL-33/ST2L positive-feedback loop and the trafficking of ST2L membrane presentation in macrophages that contribute to lung tumor progression. Mechanistically, IL-33 induces ST2L upregulation by activating NF-κB, which binds to the promoter region of the ST2L gene. Moreover, Rab37, a small GTPase involved in membrane trafficking, mediates ST2L trafficking to the plasma membrane of M2 macrophages. This IL-33/NF-κB/ST2L/Rab37 axis promotes positive-feedback loops that enhance ST2L expression and membrane trafficking in M2 macrophages. Notably, neutralizing antibodies against IL-33 or ST2L block NF-κB activity, suppress M2 macrophage polarization, and synergistically inhibit tumor growth when combined with cisplatin treatment in vitro/vivo. Clinically, Rab37+/ST2L+/CD206+ tumor-infiltrating M2 macrophages correlate with advanced-stage lung cancer patients with poor response to chemotherapy. These findings unveil a positive-feedback mechanism and provide a basis for IL-33/ST2L-targeting therapy for cancer.© 2024. The Author(s).