TGFβ signaling in the tumor microenvironment (TME) drives immune evasion and is a negative predictor of immune checkpoint inhibitor (ICI) efficacy in colorectal cancer (CRC). TIM-3, an inhibitory receptor implicated in anti-tumor immune responses and ICI resistance, has emerged as an immunotherapeutic target. This study investigated TIM-3, M2 macrophages and the TGFβ-activated TME, in association with microsatellite instability (MSI) status and consensus molecular subtypes (CMSs). Transcriptomic cohorts of CRC tissues, organoids and xenografts were examined (n= 2240). TIM-3 and a TGFβ-inducible stromal protein, VCAN, were evaluated in CRC specimens using immunohistochemistry (n= 45). TIM-3 expression on monocytes and generated M2 macrophages was examined by flow cytometry. We found that the expression ofHAVCR2(TIM-3) significantly correlated with the transcriptional signatures of TGFβ, TGFβ-dependent stromal activation and M2 macrophage, each of which were co-upregulated in CMS4, CMS1 and MSI CRCs across all datasets. Tumor-infiltrating TIM-3+immune cells accumulated in TGFβ-responsive cancer stroma. TIM-3 was increased on M2-polarized macrophages, and on monocytes in response to TGFβ treatment. In conclusion, we identified a close association between TIM-3 and M2-like polarization of macrophages in the TGFβ-rich TME. Our findings provide new insights into personalized immunotherapeutic strategies based on the TME for CRCs.
肿瘤微环境（TME）中的TGFβ信号通路驱动免疫逃逸，是结直肠癌（CRC）中免疫检查点抑制剂（ICI）疗效的负向预测因子。TIM-3作为一种与抗肿瘤免疫应答及ICI耐药相关的抑制性受体，已成为免疫治疗的新靶点。本研究探讨了TIM-3、M2型巨噬细胞及TGFβ活化的肿瘤微环境与微卫星不稳定性（MSI）状态及共识分子分型（CMS）之间的关联。研究分析了结直肠癌组织、类器官及异种移植模型的转录组数据集（n=2240），并采用免疫组织化学方法检测了CRC标本中TIM-3及TGFβ诱导的基质蛋白VCAN的表达（n=45）。通过流式细胞术检测了单核细胞及诱导生成的M2型巨噬细胞上TIM-3的表达。研究发现，HAVCR2（TIM-3）的表达与TGFβ信号特征、TGFβ依赖性基质活化及M2型巨噬细胞特征均显著相关，这些特征在所有数据集的CMS4型、CMS1型及MSI型结直肠癌中均呈现协同上调。肿瘤浸润性TIM-3阳性免疫细胞在TGFβ应答性癌基质中聚集。M2极化巨噬细胞及经TGFβ处理的单核细胞上TIM-3表达均增加。综上所述，本研究揭示了TIM-3与富含TGFβ的肿瘤微环境中巨噬细胞M2样极化之间的密切关联。这些发现为基于肿瘤微环境的结直肠癌个体化免疫治疗策略提供了新的见解。
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