WFDC3 (WAP four-disulfide core domain 3) is a serine-type endopeptidase inhibitor protein belonging to the WAP family, which functions in innate immune responses and antibacterial humoral responses 1. WFDC3 contains a conserved whey acidic protein motif characteristic of antibacterial proteins 1. The protein is constitutively expressed in reproductive tissues and is upregulated during inflammatory conditions such as lipopolysaccharide-induced epididymitis 2. WFDC3 exhibits context-dependent roles in cancer biology. In colorectal cancer, WFDC3 functions as a tumor suppressor, inhibiting metastasis through estrogen receptor β (ERβ)-mediated transcriptional repression of TGFBR1 and enhancing chemotherapy sensitivity by inhibiting ATM/ATR kinase signaling 34. However, in pancreatic adenocarcinoma, high WFDC3 expression correlates with poor prognosis, reduced immune cell infiltration (B, CD4+, and CD8+ T cells), and is associated with altered amino acid metabolism 56. In pancreatic cancer, WFDC3 promotes epithelial-mesenchymal transition and immune evasion through T cell cytotoxicity suppression 6. Clinically, WFDC3 serves as a potential prognostic biomarker in both colorectal and pancreatic cancers 35. In male fertility, WFDC3 single-knockout mice remain fertile with no obvious reproductive phenotype 7. WFDC3 was also identified as a risk gene in autoimmune disease phenotypes 8.