SHP2 as a pivotal modulator of the tumor microenvironment in gastrointestinal cancers: from mechanisms to targeted therapies

BACKGROUND: Src homology 2 domain-containing protein tyrosine phosphatase 2 (SHP2) is a critical signaling molecule involved in tumor proliferation, invasion, metastasis, and immune evasion. In gastrointestinal (GI) cancers, however, its function is highly complex and context-dependent, varying across distinct cellular compartments within the tumor microenvironment (TME). MAIN BODY: This review focuses on five major GI malignancies and reframes SHP2 function within a GI-specific TME, emphasizing how its roles are shaped by key environmental determinants-including cell type, tissue microenvironment, and disease state. We further discuss how current therapeutic modalities, such as chemotherapy, radiotherapy, and targeted therapy, modulate SHP2 activity and contribute to treatment resistance. In addition, we evaluate the therapeutic potential of SHP2 inhibition, highlighting recent advances in allosteric inhibitors, emerging combination strategies, and ongoing clinical studies. CONCLUSIONS: Together, this review provides a conceptual framework for understanding SHP2 as both a signaling integrator and a precision therapeutic target in GI cancers, offering insights that may inform future mechanistic studies and the development of context-aware therapeutic strategies.