VCX3A is an X-linked cancer/testis antigen with emerging roles in both germ cell development and oncology. VCX3A functions as a DNA methylation-dependent gene, predominantly expressed in testicular tissue and aberrantly activated in multiple cancer types 1. In normal physiology, VCX3A may participate in spermatogenesis, as whole-genome sequencing identified novel VCX3A variants in patients with nonobstructive azoospermia 2. Mechanistically, VCX3A is regulated by histone modifications; in pediatric high-grade gliomas harboring H3.3K27M mutations, decreased H3K27me3 and increased H3K4me3 at the VCX3A promoter drive its upregulation 3. VCX3A knockdown significantly inhibited glioma cell growth, and VCX3A overexpression stimulated HLA gene expression, suggesting immune regulatory functions 3. Clinically, VCX3A is expressed in approximately 20-35% of lung cancers as a potential immunotherapeutic target 4. Deletions encompassing VCX3A occur in X-linked ichthyosis and have been associated with mental retardation in some patients with complex deletions involving multiple genes 5, 6, though VCX3A deletion alone appears insufficient for cognitive phenotypes. VCX3A represents a promising biomarker and therapeutic target in pediatric gliomas and lung cancers.