In this regard, anti-PD-1/PD-L1 therapies elicit potent antitumor responses against epithelial cSCCs by reversing the exhausted state of CD8+ T cells, mesenchymal cSCCs respond to anti-CTLA-4 and anti-TIGIT therapies in a CD8+ and NK cell-dependent manner, and combined ICB therapies are more effective against cSCCs enriched in epithelial, hybrid E/M, and mesenchymal cancer cells by stimulating the activity of both CTLs and NK cells. The gene discussed is TIGIT; the disease is cancer.