SLC9A2 encodes a plasma membrane Na+/H+ antiporter that mediates electroneutral exchange of intracellular H+ for extracellular Na+ 1. The protein contains 698 amino acids with 10 transmembrane domains and is widely distributed in gastrointestinal tract, kidney, heart, and other tissues 2. In colonic epithelium, SLC9A2 regulates intracellular pH and participates in short-chain fatty acid absorption through coupled Na+ transport mechanisms 3. Mechanistically, SLC9A2 functions as a tumor suppressor in multiple cancer types. In colorectal cancer (CRC), SLC9A2 inhibits epithelial-mesenchymal transition by suppressing STAT3 signaling and reduces VEGFA secretion to normalize tumor vasculature 4. SLC9A2 also suppresses proliferation, migration, and invasion through MAPK pathway inhibition 5. In osteosarcoma, SLC9A2 overexpression restrains cell growth and invasion by inhibiting aerobic glycolysis, with expression regulated by transcription suppressor ETS1 6. In kidney clear cell carcinoma, zDHHC3-mediated S-palmitoylation of SLC9A2 regulates apoptosis 7. Clinically, reduced SLC9A2 expression correlates with advanced TNM staging in CRC and associates with immunotherapy resistance 4. Higher SLC9A2 expression predicts improved treatment responses. These findings establish SLC9A2 as a potential prognostic biomarker and therapeutic target across multiple malignancies.