Comprehensive pan-cancer characterization of cancer-testis genes at single-cell resolution

Cancer-testis genes (CTGs) represent promising therapeutic targets due to their restricted expression in the testis and aberrant activation in cancers. However, their expression, regulation, and clinical relevance have not been systematically characterized at single-cell resolution. Here, by integrating large-scale single-cell transcriptomic datasets across 12 cancer types, we identified 407 CTGs. Autosomal CTGs exhibited broader expression across samples than those on the X chromosome. CTG activation in malignant cells was closely linked to epigenetic regulation, with chromatin remodelers ARID4B and YEATS2 playing pivotal roles. Malignant cells consistently expressed a greater number of CTGs across cancer types, which led us to develop a computational pipeline for rapid malignancy annotation. Clinically, several CTGs showed potential as targets for T-cell receptor-engineered T-cell (TCR-T) therapy. Furthermore, CTG activation appeared to foster an immune-evasive tumor microenvironment. Collectively, we established a single-cell atlas of CTGs, deepening mechanistic understanding and facilitating their translational application in cancer treatment.