Liu P, Chen J. Targeting SHP2: Dual breakthroughs in colorectal cancer therapy–from signaling pathway modulation to immune microenvironment remodeling. World J Gastrointest Oncol 2025; 17(7): 107380 [DOI: 10.4251/wjgo.v17.i7.107380]
Corresponding Author of This Article
Jia Chen, Clinical Assistant Professor (Honorary), Department of Pulmonary and Critical Care Medicine, Zhuji Central Hospital, No. 98 Zhugong Road, Zhuji 311800, Zhejiang Province, China. 13357530129@163.com
Research Domain of This Article
Oncology
Article-Type of This Article
Minireviews
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Gastrointest Oncol. Jul 15, 2025; 17(7): 107380 Published online Jul 15, 2025. doi: 10.4251/wjgo.v17.i7.107380
Targeting SHP2: Dual breakthroughs in colorectal cancer therapy–from signaling pathway modulation to immune microenvironment remodeling
Pan Liu, Jia Chen
Pan Liu, Department of Pathology, Zhejiang Cancer Hospital, Hangzhou 310022, Zhejiang Province, China
Jia Chen, Department of Pulmonary and Critical Care Medicine, Zhuji Central Hospital, Zhuji 311800, Zhejiang Province, China
Author contributions: Liu P wrote the manuscript; Chen J conceptualized the manuscript and oversaw the writing of the manuscript.
Supported by Zhejiang Provincial Natural Science Foundation for Youths, No. QN25H160012; and Zhejiang Medical and Health Science and Technology Plan, No. 2023RC006.
Conflict-of-interest statement: The authors declare that they have no conflicts of interest pertaining to the subject matter discussed in this paper.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jia Chen, Clinical Assistant Professor (Honorary), Department of Pulmonary and Critical Care Medicine, Zhuji Central Hospital, No. 98 Zhugong Road, Zhuji 311800, Zhejiang Province, China. 13357530129@163.com
Received: March 24, 2025 Revised: April 17, 2025 Accepted: May 30, 2025 Published online: July 15, 2025 Processing time: 114 Days and 21.4 Hours
Abstract
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.
Core Tip: This paper summarizes the regulatory mechanisms of SHP2 in colorectal cancer (CRC) and emerging therapeutic strategies targeting SHP2. The findings demonstrated that SHP2 serves as a master oncogenic regulator in CRC pathogenesis by coordinating receptor tyrosine phosphatase-mediated signaling. Notably, SHP2 remodels the tumor immune microenvironment by modulating macrophage and T cell functions. Allosteric SHP2 inhibitors, which are characterized by high oral bioavailability and potent target specificity, are currently under evaluation in multicenter phase I/II trials. Although acquired resistance remains challenging, combination strategies, particularly immunotherapy-based treatments, have shown transformative potential, accelerating the transition of SHP2-targeted therapies and offering novel paradigms for personalized CRC treatment.
