ICOS (inducible T cell costimulator) is a stimulatory receptor expressed on activated T cells that delivers costimulatory signals upon binding to its ligand ICOSL on antigen-presenting cells. This interaction enhances T-cell proliferation, cytokine secretion (including IL-10), and promotes effective antibody responses by B cells. ICOS also plays a critical role in differentiating T follicular regulatory cells during immune challenges such as viral infection. Mechanistically, ICOS potentiates T-cell receptor-induced calcium flux through PLCG1 activation and independently activates PI3K signaling pathways. The receptor is essential for CD40-mediated immunoglobulin class switching and prevents apoptosis of pre-activated T cells. ICOS dysfunction associates with combined immunodeficiency, autoimmune hepatitis, and type 1 diabetes. A non-coding risk variant (rs117701653) in the ICOS locus increases ICOS expression in memory CD4+ T cells, accelerating differentiation into T peripheral helper cells and contributing to rheumatoid arthritis and type 1 diabetes pathogenesis 1. Clinically, ICOS agonists including vopratelimab and feladilimab are in development for cancer immunotherapy; however, vopratelimab monotherapy and combination with nivolumab showed modest objective response rates (1.4% and 2.3%, respectively) in advanced solid tumors, with clinical benefit observed only in patients who developed ICOS-high CD4+ T cells 2. ICOS-enhanced CAR-T cells targeting B7H3 demonstrated durable eradication of triple-negative breast cancer and metastasis in preclinical models 3.