ITGB2 serves as a key integrin that drives immune cell activation and migration. It has long been regarded as expressed solely in hematopoietic cells. As a result, the potential role of ITGB2 expressed within cancer cells themselves in the advancement and treatment of solid tumors has received limited attention. We employed single-cell and bulk RNA sequencing, real-time quantitative PCR, multiplex immunofluorescence, flow cytometry, immunoblotting, and ICAM-1-dependent adhesion and proliferation assays. These approaches helped reveal functional ITGB2 expression intrinsic to melanoma cells, its links to clinical tumor progression, its activation status, its role in protumorigenic signaling, and its roles in adhesion and proliferation. Analyses were conducted using patient melanoma samples and established human and murine melanoma cell lines. In vivo tumorigenicity experiments were carried out in immunocompromised NSG mice, immunocompetent wild-type C57BL/6 mice, and Icam1 knockout C57BL/6 mice to examine the downstream effects of the melanoma-ITGB2 pathway on tumor growth and metastasis. The cancer cell-intrinsic ITGB2 pathway was inhibited through CRISPR/Cas9-generated Itgb2 knockout, ITGB2-blocking antibodies, ITGB2 activation via CD44 crosslinking, and pharmacologic blockade of ITGB2-linked Wnt signaling using LGK974, zamaporvint, and the FDA-approved agent pyrvinium pamoate repurposed for oncology. The findings establish that ITGB2 is expressed outside the hematopoietic compartment and exerts protumorigenic effects directly within melanoma cells. Melanoma cell ITGB2 facilitated binding to ICAM-1, enhanced cancer progression in preclinical models, showed higher levels in clinical metastatic melanomas compared with primary tumors or benign nevi, and served as a predictor of sentinel lymph node metastasis in patients with primary melanoma. In line with this, blocking melanoma cell-intrinsic ITGB2 with antibodies or Itgb2 gene knockout strongly reduced ICAM-1-mediated adhesion, tumor growth, and metastatic spread. The interaction between melanoma cell ITGB2 and ICAM-1 triggered downstream Wnt signaling; pharmacologic suppression of this pathway inhibited ITGB2-driven tumorigenesis in melanoma. This study challenges the established view that ITGB2 expression is confined to leukocytes by identifying a tumor cell-intrinsic ITGB2:ICAM-1:Wnt signaling axis that promotes tumor growth and represents a genuine therapeutic target in melanoma.
