ICOSLG encodes the ligand for inducible T cell costimulator (ICOS), a B7-family costimulatory molecule critical for adaptive immunity. The protein binds ICOS on activated T cells to promote T cell proliferation and cytokine production, and also stimulates B cell differentiation into plasma cells 12. In endothelial cells, ICOSLG facilitates neutrophil transmigration in response to inflammatory signals. Autosomal recessive ICOSLG mutations cause combined immunodeficiency marked by recurrent respiratory tract infections and DNA-virus susceptibility at epithelial barriers, including human papillomavirus 3. This demonstrates the critical role of the ICOSL:ICOS axis in mucocutaneous immunity. At the population level, ICOSLG exhibits modest constraint (gnomAD pLI≈0.3–0.5), reflecting the viability of some heterozygous carriers; however, biallelic loss-of-function variants cause clinically significant immunodeficiency. In cancer, ICOSLG overexpression promotes progression through multiple mechanisms. In glioblastoma, ICOSLG expression by mesenchymal tumor cells expands interleukin-10-producing T cells that suppress antitumor immunity 4. In gastric cancer, ICOSLG drives glycolysis and cell proliferation 5. Conversely, ICOSL+ B cells emerging after chemotherapy enhance anti-tumor immunity by boosting the effector-to-regulatory T cell ratio 6. ICOSLG expression also predicts response to anti-PD-1 checkpoint inhibition combined with antihistamine therapy in advanced melanoma 7. AMG-557, a clinical-stage ICOS agonist, represents a therapeutic approach targeting this pathway.