TGM4 (transglutaminase 4) is a prostate-specific cross-linking enzyme with critical roles in male reproduction and emerging importance as an immunotherapy target. The gene spans approximately 35 kb with 13 exons and displays prostate-restricted expression 1. TGM4 catalyzes protein cross-linking and polyamine conjugation in the seminal tract, essential functions for reproductive physiology 1. Mechanistically, TGM4 expression is regulated by an Sp1/Sp3 binding motif in its promoter 2. Clinically, TGM4 dysfunction is implicated in male subfertility through autoimmune mechanisms. In autoimmune polyendocrine syndrome type 1 (APS1), TGM4 becomes a male-specific autoantigen following prostate maturation, triggering autoantibodies that correlate with destructive prostatitis and compromised TGM4 secretion 3. Furthermore, TGM4 represents a novel immunogenic prostate-restricted tumor-associated antigen for cancer immunotherapy. Elevated TGM4 expression in primary prostate cancers correlates with unfavorable prognosis 4. TGM4-pulsed dendritic cells elicit stronger CD8 and CD4 T-cell responses compared to established antigens PAP and PSA, with 30% of vaccinated patients developing anti-TGM4 antibodies 4. TGM4 is downregulated in prostate cancer tissues, identifying it as a potential diagnostic biomarker 5.