Rewiring the tumor microenvironment: IGFBP2 at the Nexus of remodeling and therapy resistance?

Insulin-like growth factor binding protein 2 (IGFBP2) has emerged as a multifarious and context-dependent oncoprotein that links several mechanisms in the tumor microenvironment (TME) including oncogenic signaling, extracellular matrix (ECM) remodeling, immune evasion, and therapy resistance. Beyond its established role in modulating IGF signaling, IGFBP2 exerts IGF-independent effects via its RGD integrin-binding motif and nuclear localization signal (NLS). By binding integrins (αvβ3, α5β1), IGFBP2 activates focal adhesion kinase (FAK), which then triggers PI3K/AKT signaling and MAPK/ERK signaling pathways, resulting in enhanced proliferation, migration, invasion, and angiogenesis. Nuclear translocation of IGFBP2, mediated by its NLS, enables direct regulation of gene expression, notably by upregulating epithelial-mesenchymal transition (EMT) transcription factors such as ZEB1, SNAI1, and TWIST1, and regulating immune checkpoint molecules. These actions reshape the TME by increasing angiogenesis, stromal stiffness, and tumor invasiveness. IGFBP2 further sustains survival signals under receptor tyrosine kinase inhibition, enhances tumor cell metabolic adaptation to hypoxia, and supports cancer stemness, all of which drive resistance to chemotherapy, radiotherapy, and immunotherapy. Overexpression of IGFBP2 in cancer is linked to increased tumor aggressiveness, unfavorable prognosis, and general resistance to therapy. Importantly, IGFBP2 functions are highly context-dependent, in some epithelial settings, IGFBP2 sequesters IGFs and dampens IGF-IR signaling, resulting suppression of downstream oncogenic pathways. This duality underscores IGFBP2's nuance and tumor-specific biology. Therapeutic strategies under development specifically target IGFBP2-integrin-mediated signaling and IGFBP2 nuclear activity. There are encouraging results in preclinical studies involving antisense oligonucleotides, monoclonal antibodies, and peptide inhibitors. As both a mediator of oncogenic adaptation and a clinical biomarker, IGFBP2 represents a vulnerability in the TME that may be targeted to improve, personalize, and combine cancer therapies.