Liu Pan, Chen Jia
Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, China.
Department of Pulmonary and Critical Care Medicine, Zhuji Central Hospital, Zhuji 311800, Zhejiang Province, China.
World J Gastrointest Oncol. 2025 Jul 15;17(7):107380. doi: 10.4251/wjgo.v17.i7.107380.
SHP2 is the first identified oncogenic tyrosine phosphatase that promotes colorectal cancer (CRC) progression, and it is consistently overexpressed in CRC. It facilitates CRC oncogenesis by mediating downstream signaling cascades of receptor tyrosine kinases, including the RAS/ERK, JAK/STAT, and PI3K/AKT pathways, which are clinically associated with poor prognosis. Furthermore, SHP2 orchestrates immunosuppressive signaling networks by impairing cytotoxic T cell infiltration and changing the phenotype of tumor-associated macrophages within the tumor microenvironment (TME). Targeting SHP2 represents a dual therapeutic strategy in CRC: It concurrently regulates RTK signaling and reprograms the immunosuppressive TME. SHP2 inhibitors, administered both as monotherapy and in combination regimens, have advanced into clinical trial phases. Consequently, SHP2 serves as both a molecular target for precision oncology and an immunomodulatory node, positioning it as a high-priority candidate for CRC treatment.
SHP2是首个被鉴定出的促进结直肠癌（CRC）进展的致癌性酪氨酸磷酸酶，且在CRC中持续过表达。它通过介导受体酪氨酸激酶的下游信号级联反应促进CRC肿瘤发生，这些信号级联反应包括RAS/ERK、JAK/STAT和PI3K/AKT通路，临床上这些通路与预后不良相关。此外，SHP2通过损害细胞毒性T细胞浸润和改变肿瘤微环境（TME）中肿瘤相关巨噬细胞的表型来协调免疫抑制信号网络。靶向SHP2代表了CRC的一种双重治疗策略：它同时调节RTK信号并重新编程免疫抑制性TME。SHP2抑制剂，无论是作为单一疗法还是联合方案给药，都已进入临床试验阶段。因此，SHP2既是精准肿瘤学的分子靶点，也是免疫调节节点，使其成为CRC治疗的高优先级候选靶点。
