The insulin-like growth factor 1 receptor (IGF1R) is a transmembrane tyrosine kinase receptor that plays a critical role in regulating cell growth, proliferation, survival, and metabolism. Structurally, it consists of two extracellular α-subunits for ligand binding and two transmembrane β-subunits with kinase activity. Upon activation by ligands (IGF-1. IGF-2. or insulin at high concentrations), IGF1R initiates downstream signaling pathways, including PI3K-AKT and RAS-MAPK, which are frequently dysregulated in cancer. Overexpression or aberrant activation of IGF1R is implicated in tumorigenesis, metastasis, and resistance to therapies in various cancers, such as breast, colorectal, and lung cancers.
IGF1R-targeting antibodies are therapeutic agents designed to block ligand-receptor interactions or receptor dimerization, thereby inhibiting oncogenic signaling. Early monoclonal antibodies (e.g., cixutumumab, figitumumab) showed preclinical promise but faced mixed clinical outcomes due to tumor heterogeneity, compensatory signaling (e.g., via insulin receptor isoforms), and toxicity concerns. Recent strategies focus on combination therapies (e.g., with chemotherapy or immune checkpoint inhibitors) or antibody-drug conjugates to enhance efficacy. Challenges remain in patient stratification and overcoming resistance mechanisms. Despite setbacks, IGF1R remains a compelling target, with ongoing research exploring bispecific antibodies and predictive biomarkers to refine its therapeutic potential in precision oncology.