Work

Enhanced tumor metastasis driven by the crosstalk between melanoma cells and tumor-associated macrophages: insights into the CXCL10/CXCR3-hnRNP C-MIF axis

Year: 2026

Type: article

Abstract: Background Tumor-associated macrophages (TAMs) are critical drivers in melanoma growth and metastasis orchestrating complex cellular interactions within the tumor microenvironment (TME). While the RNA-binding protein heterogeneous nuclear ribonucleoprotein C1/C2 (hnRNP C) has been linked to melanoma progression and immune evasion, its specific role in macrophage-tumor communication and TME remodeling remains poorly understood.Methods Multiple publicly available melanoma datasets (TCGA-SKCM, GSE8401, GSE46517, and single-cell RNA sequencing) were analyzed to map hnRNP C-associated signaling pathways, and macrophage-tumor interactions. Ligand-receptor cell communication analysis was used to characterize networks within the TME. Functional studies were conducted in melanoma cell lines (Buf1379, Buf1402, Buf836) following siRNA-mediated hnRNP C knockdown using wound healing and trans-well assays to assess cell migration and invasion. Macrophage-tumor interactions were comprehensively studied via trans-well co-culture models, flow cytometry, cytokine profiling, and recombinant CXCL10 stimulation assays. Protein-level validation and clinical relevance were assessed using multicohort datasets and immunohistochemistry.Results Elevated hnRNP C expression significantly enhanced melanoma cell migration, invasion, and epithelial-mesenchymal transition (EMT)-associated programs. Mechanistically, hnRNP C-high melanoma cells secreted increased levels of the macrophage migration inhibitory factor (MIF), which reprogrammed macrophages toward an interferon-associated TAM (IFN-TAM) phenotype. Moreover, CXCL10 via CXCR3 activation upregulated hnRNP C expression in melanoma cells establishing a bidirectional feedback loop. Single-cell transcriptomic analyses confirmed enriched MIF-mediated signaling between macrophages and melanoma cells. Spatially, this macrophage-derived CXCL10/CXCR3-hnRNP C-MIF signaling axis promoted macrophage remodeling and drove metastatic tumor states. A three-gene prognostic signature (hnRNP C-MIF-CXCR3) showed robust predictive performance across independent melanoma cohorts and strongly correlated with tumor stage, metastatic status, and overall survival. Protein-level validation confirmed elevated hnRNP C and MIF expression in melanoma tissues compared with normal skin.Conclusions This study identifies a novel macrophage-tumor signaling circuit in melanoma, wherein CXCL10/CXCR3-driven hnRNP C activation promotes MIF-mediated macrophage reprogramming and subsequent metastatic progression. The identified three-gene signature provides a clinically relevant prognostic biomarker and highlights hnRNP C as a promising therapeutic target for disrupting macrophage-driven tumor progression.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-015594