S100A4: A calcium-binding protein at the crossroads of cancer, fibrosis, and antiviral immunity.

S100A4 is a calcium-binding protein and plays critical roles in cellular migration, cytoskeletal dynamics by directly interacting with the actomyosin cytoskeleton and functioning extracellularly as a damage-associated molecular pattern (DAMP). In this review, we summarize molecular and structural characteristics of S100A4, including key functional residues and conformational changes induced by calcium binding. Importantly, we detail how S100A4 exerts its functions: intracellularly, it binds to non-muscle myosin IIA to disrupt filament assembly and facilitates p53 degradation; extracellularly, it binds receptors such as RAGE and TLR4 to strongly activate NF-κB and MAPK signaling. Consequently, overexpressed S100A4 is widely established as a poor prognostic marker that drives cancer metastasis, fibrotic tissue remodeling, and severe chronic inflammation. Furthermore, current studies demonstrate S100A4 exhibits immunomodulatory properties and potentially functions as an effective mucosal vaccine adjuvant capable of enhancing both mucosal and systemic immune responses. Ultimately, our synthesis underscores a critical duality: while S100A4 must be aggressively targeted to halt its detrimental roles in tumor metastasis and tissue fibrosis, its potent immunomodulatory properties simultaneously present an underexplored, highly beneficial opportunity for developing next-generation mucosal vaccine adjuvants.