19–21 We recently demonstrated enhanced persistence combined with reduced signs of exhaustion within the MSLN-CAR T cells carrying a 4–1BB co-stimulatory domain compared to CD28-containing MSLN-CARs in a preclinical in vivo orthotopic model of ovarian cancer.22 To overcome the difficulties posed by the complex high-grade serous ovarian cancer niche, it is crucial to investigate the mechanisms influencing CD28- and 4–1BB co-stimulated CAR T cell functionality. This evidence concerns the gene CD28 and ovarian cancer.