The composition of immune infiltrates strongly affects the prognosis of patients with colorectal cancer (CRC). Interleukin (IL)-33 and regulatory T cells (Tregs) in the tumor microenvironment have been separately implicated in CRC; however their contribution to intestinal carcinogenesis is still controversial. Here, we reveal that IL-33 signaling promotes CRC by changing the phenotype of Tregs. In mice with CRC, tumor-infiltrating Tregs preferentially upregulate IL-33 receptor (ST2), and IL-33/ST2 signaling positively correlates with tumor number and size. Transcriptomic and flow cytometry analyses demonstrate that ST2 expression induces a more activated and migratory phenotype in FOXP3⁺ Tregs, which favors their accumulation in the tumor environment. Consequently, genetic ablation of St2 reduces Treg infiltration and concomitantly enhances the frequencies of effector CD8⁺ T cells, thereby restraining CRC. Mechanistically, IL-33 curtails IL-17 production by FOXP3⁺ Tregs and inhibits Th17 differentiation. In humans, numbers of activated ST2-expressing Tregs are increased in blood and tumor lesions of CRC patients, suggesting a similar mode of regulation. Together, these data indicate a central role of IL-33/ST2 signaling in shaping an immunosuppressive environment during intestinal tumorigenesis. Blockade of this pathway may provide a strategy to modulate the composition of CRC immune infiltrates.

免疫浸润的组成强烈影响结直肠癌 (CRC) 患者的预后。肿瘤微环境中的白细胞介素 (IL)-33 和调节性 T 细胞 (Treg) 分别与 CRC 相关；然而，它们对肠道致癌作用的贡献仍然存在争议。在这里，我们揭示了 IL-33 信号通过改变 Tregs 的表型来促进 CRC。在患有 CRC 的小鼠中，肿瘤浸润性 Treg 优先上调 IL-33 受体 (ST2)，并且 IL-33/ST2 信号与肿瘤数量和大小呈正相关。转录组学和流式细胞术分析表明，ST2 表达在 FOXP3 ⁺ Tregs 中诱导更活跃和迁移的表型，这有利于它们在肿瘤环境中的积累。因此，St2的基因消融减少 Treg 浸润并同时增加效应 CD8 ⁺ T 细胞的频率，从而抑制 CRC。从机制上讲，IL-33 减少 FOXP3 ⁺ Treg 产生 IL-17 并抑制 Th17 分化。在人类中，CRC 患者的血液和肿瘤病变中激活的表达 ST2 的 Treg 的数量增加，表明存在类似的调节模式。总之，这些数据表明 IL-33/ST2 信号在肠道肿瘤发生过程中塑造免疫抑制环境中的核心作用。阻断该通路可能提供一种策略来调节 CRC 免疫浸润的组成。