Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING–TBK1–IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68⁺ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

结直肠癌 (CRC) 是一种世界范围内的恶性肿瘤，由微卫星不稳定性 (MSI) 和稳定 (MSS) 表型组成。尽管 SHP2 是癌症治疗的一个有希望的靶点，但它与先天免疫抑制的关系仍然难以捉摸。为了解决这个问题，进行了单细胞 RNA 测序，以探索 SHP2 在来自小鼠 MC38 异种移植物的所有细胞类型的肿瘤微环境 (TME) 中的作用。发现瘤内细胞在功能上是异质的，并且对 SHP099（一种 SHP2 变构抑制剂）有显着反应。SHP099显着抑制了肿瘤细胞的恶性进化。机制上，STING-TBK1-IRF3 介导的 I 型干扰素信号传导在浸润的骨髓细胞中被 SHP099 高度激活。尤其，⁺巨噬细胞比 MSI 高表型，表明巨噬 SHP2 在 TME 中的潜在作用。总的来说，我们的数据揭示了一种由 SHP2 介导的先天免疫抑制机制，表明 SHP2 是结肠癌免疫治疗的一个有希望的靶点。