IGF2 is a paternally expressed growth factor with pleiotropic developmental and metabolic functions. Structurally, it contains cysteine residues critical for disulfide bonding; mutations affecting these residues impair protein function 1. Primary functions include regulating prenatal and postnatal growth 2, with tissue-specific and developmental stage-dependent effects. IGF2 signals through IGF1R and insulin receptor pathways, activating PI3K/AKT cascades 3. Clinically, IGF2 deficiency causes Silver-Russell syndrome (SRS), characterized by intrauterine growth restriction, feeding difficulties, and cardiovascular anomalies 1. Conversely, dysregulated IGF2 expression contributes to tumor progression. Recent studies reveal IGF2 secreted by cancer-associated fibroblasts promotes T cell exclusion via CXCL12 and PD-L1 upregulation, conferring immunotherapy resistance 3. Additionally, tobacco smoke-induced hyperglycemia increases IGF2 in tumor-associated macrophages, which paracrinally activates insulin receptor on cancer cells to promote PD-L1 expression and lung cancer progression 4. IGF2 expression is tightly regulated through imprinted gene mechanisms and epigenetic modifications. DNA methylation patterns at the IGF2 locus are established periconceptionally and persist throughout life 5, with altered methylation implicated in preeclampsia pathogenesis 6. Paxillin regulates IGF2 transcription through long-range chr11 interactions with distal enhancers 7. These regulatory mechanisms underscore IGF2's critical role in fetal development and disease pathogenesis.