S100A16 is a calcium-binding protein belonging to the S100 family, characterized by two EF-hand motifs with a single functional Ca2+ binding site in the C-terminal domain 1. As a 103-amino acid protein widely expressed across human tissues, particularly in epithelial-rich tissues, S100A16 functions primarily as a regulator of cellular proliferation, migration, and invasion 2. Mechanistically, S100A16 executes its tumor-promoting functions through multiple signaling pathways. In prostate cancer, it activates AKT and ERK signaling while downregulating tumor suppressors p21 and p27 3. In pancreatic cancer, S100A16 induces epithelial-mesenchymal transition (EMT) via TWIST1 upregulation and STAT3 pathway activation 4. In cervical cancer stem-like cells, S100A16 positively regulates pluripotency factors Oct4 and Nanog through proteasome-dependent mechanisms 5. S100A14 can regulate S100A16 protein levels post-transcriptionally 6. S100A16 is aberrantly expressed in multiple cancer types, displaying both tumor-promoting roles in breast, prostate, lung, and pancreatic cancers, and suppressive roles in oral cancer and acute lymphoblastic leukemia 1. In lung adenocarcinoma progression, S100A16 serves as a key prognostic biomarker and therapeutic target 7, with clinical significance in predicting immunotherapy response and chemotherapy sensitivity.