Enhanced tumor metastasis driven by the crosstalk between melanoma cells and tumor-associated macrophages: insights into the CXCL10/CXCR3-hnRNP C-MIF axis
- 1Institute of Pathology, Section Immunopathology, Martin Luther University of Halle-Wittenberg, Halle (Saale), Germany
- 2Institute of Translational Immunology, Brandenburg Medical School “Theodor Fontane”, Brandenburg an der Havel, Germany
- 3Department of Pathology, The Affiliated Hospital, Southwest Medical University, Luzhou, China
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.
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BibTeX
@article{wang2026enhanced,
title = {{Enhanced tumor metastasis driven by the crosstalk between melanoma cells and tumor-associated macrophages: insights into the CXCL10/CXCR3-hnRNP C-MIF axis}},
author = {Yuan Wang and Chiara Massa and Gowtham Chowdary Tammineni and Kamatchi Ulagappan and Bo Yang and Dimitrios Kokoretsis and Yiyang Zhao and Karthikeyan Subbarayan and Barbara Seliger},
journal = {Journal for Immunotherapy of Cancer},
year = {2026},
month = oct,
doi = {10.1136/jitc-2026-015594},
url = {https://doi.org/10.1136/jitc-2026-015594},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Enhanced tumor metastasis driven by the crosstalk between melanoma cells and tumor-associated macrophages: insights into the CXCL10/CXCR3-hnRNP C-MIF axis
AU - Yuan Wang
AU - Chiara Massa
AU - Gowtham Chowdary Tammineni
AU - Kamatchi Ulagappan
AU - Bo Yang
AU - Dimitrios Kokoretsis
AU - Yiyang Zhao
AU - Karthikeyan Subbarayan
AU - Barbara Seliger
PY - 2026
DA - 2026/10/30
JO - Journal for Immunotherapy of Cancer
DO - 10.1136/jitc-2026-015594
UR - https://doi.org/10.1136/jitc-2026-015594
AB - 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.
SN - 2051-1426
ER -