IFNGR1 (interferon gamma receptor 1) is the ligand-binding subunit of the type-II interferon receptor, which functions as a critical component of antimicrobial, antiviral, and antitumor immune responses 1. The receptor forms a functional heterodimeric complex with IFNGR2 upon interferon-gamma binding 1. Upon ligand engagement, IFNGR1's intracellular domain recruits and activates JAK1 and JAK2 kinases, which phosphorylate IFNGR1 to create docking sites for STAT1, leading to STAT1 phosphorylation, dimerization, nuclear translocation, and transcriptional activation of target genes 2. IFNGR1 is post-translationally regulated through ubiquitination-dependent proteasomal degradation and palmitoylation-dependent lysosomal sorting, mechanisms that fine-tune immune responses 23. Clinically, IFNGR1 dysfunction is associated with Immunodeficiency 27A/B, while germline loss-of-function causes severe susceptibility to mycobacterial infections. IFNGR1 expression stability is therapeutically targetable: enhancing IFNGR1 stability through N-glycosylation augmentation or palmitoylation inhibition restores interferon-gamma sensitivity in colorectal cancer cells and improves immunotherapy efficacy 43. Additionally, IFNGR1 signaling is required for CAR T cell-mediated killing of solid tumors but not hematologic malignancies, and genetic polymorphisms in IFNGR1 associate with tuberculosis susceptibility in population-specific manners 56.