蛋白磷酸酶SHP2/PTPN11已被报道为多种恶性肿瘤增殖途径的关键调节因子。有趣的是，SHP2也被描述为肿瘤微环境的重要调节因子。基于这些证据，SHP2在癌症中被认为是一个多方面的靶点，促使了直接抑制剂的开发，这将提供肿瘤内在和外在抑制的双重益处。在本综述中，我们将讨论SHP2在癌症和肿瘤微环境中的作用，以及临床上使用SHP2抑制剂作为组合药物来改善治疗反应的策略。SHP2磷酸酶具有多效因子的功能，其抑制不仅可以阻碍肿瘤生长，还可以重塑肿瘤微环境。尽管它们作为单一药物的活性可能有限，SHP2抑制剂有潜力成为关键的组合药物，以增强肿瘤对治疗的深度和持久性反应。©2023 The Authors; Published by the American Association for Cancer Research.

The protein phosphatase SHP2/PTPN11 has been reported to be a key modulator of proliferative pathways in a wide range of malignancies. Intriguingly, SHP2 has also been described as a critical regulator of the tumor microenvironment. Based on this evidence SHP2 is considered a multifaceted target in cancer, spurring the notion that the development of direct inhibitors of SHP2 would provide the twofold benefit of tumor intrinsic and extrinsic inhibition. In this review, we will discuss the role of SHP2 in cancer and the tumor microenvironment, and the clinical strategies in which SHP2 inhibitors are leveraged as combination agents to improve therapeutic response.The SHP2 phosphatase functions as a pleiotropic factor, and its inhibition not only hinders tumor growth but also reshapes the tumor microenvironment. Although their single-agent activity may be limited, SHP2 inhibitors hold the potential of being key combination agents to enhance the depth and the durability of tumor response to therapy.©2023 The Authors; Published by the American Association for Cancer Research.