ICOS/ICOSL pathway activation has been observed in multiple cancer types6; thus, ICOS-modulating agents are under development in combination with Food and Drug Administration (FDA)-approved immune checkpoint inhibitors (ICIs) to improve responses and outcomes in advanced and metastatic cancers.1 ICOS-targeting therapies are being studied in combination with CTLA-4, PD-1, or PD-L1 antibodies.1,12, , , , , , –19 Given that ICOS/ICOSL pathway activation can both stimulate and inhibit the immune system, developing appropriate targets and therapeutics can be challenging. The gene discussed is CD274; the disease is cancer.