TM4SF1 is a transmembrane tetraspanin family member that functions as a signal transducer regulating multiple oncogenic processes across multiple cancer types. 1 As a cell surface-associated membrane protein with four transmembrane domains, TM4SF1 participates in cell adhesion, activation, and invasion through formation of tetraspanin-enriched microdomains. 2 Mechanistically, TM4SF1 promotes cancer progression through multiple pathways: in colorectal cancer, it enhances epithelial-to-mesenchymal transition (EMT) and cancer stemness via the Wnt/β-catenin/c-Myc/SOX2 axis; 3 in esophageal squamous cell carcinoma, it interacts with integrin α6 to promote cell migration and invasion through the FAK signaling pathway in a laminin-dependent manner; 4 and in hepatocellular carcinoma, it suppresses senescence by enhancing AKT phosphorylation through interaction with PDPK1. 5 Clinically, TM4SF1 is consistently upregulated across multiple epithelial cancers—colorectal, gastric, esophageal, and hepatocellular carcinoma—and correlates with poor prognosis and advanced TNM staging. 34 Importantly, TM4SF1 serves as a conserved cell surface marker for alveolar epithelial progenitor cells in human lung regeneration. 6 TM4SF1 depletion sensitizes tumors to anti-PD-1 immunotherapy by promoting senescence and restoring CD8+ T cell cytotoxic function, 5 identifying it as a promising therapeutic target, particularly in combination immunotherapy approaches.