Researchers reveal mechanism of SHP2-mediated tumor immunosuppression

Colorectal cancer (CRC), a malignant tumor worldwide, consists of microsatellite (MSI) and stable instability (MSS) phenotypes. Although SHP2 is a promising target for cancer treatment, its relationship to innate immunosuppression remains elusive.

To address this problem, the authors of this article performed unicellular RNA sequencing to explore the role of SHP2 in all tumor microenvironment (TME) cell types from MC38 murine xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, an allosteric inhibitor of SHP2.

The malignant development of tumor cells was remarkably arrested by SHP099. Mechanically, STING-TBK1-IRF3-mediated type I interferon signaling was strongly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with an MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68.⁺macrophages than MSI-high phenotypes, suggesting the potential role of SHP2 macrophage in TME.

Collectively, the authors’ data reveal a mechanism of innate SHP2-mediated immunosuppression, suggesting that SHP2 is a promising target for colon cancer immunotherapy.