GM-CSF, a myeloid-priming cytokine, exhibits context-dependent effects on tumor growth and, despite its clinical use, its role in human melanoma remains undefined.

A stage II-IV primary melanoma cohort (n = 80) was interrogated for GM-CSF/GM-CSFR expression at the single-cell level in tumor-associated macrophages (TAMs) and tumor cells (TCs). Invasion, survival and lung colonization assays were used to determine the pro-tumoral role of GM-CSF, and RNA-seq to analyze transcriptomic profiles.

GM-CSF was significantly enriched in TAMs and TCs of primary cutaneous melanoma samples from patients who subsequently developed metastasis, compared with non-metastasizing ones, correlating with reduced disease-free and overall survival (p < 0.0001). GM-CSF receptor subunits were present in both cell types and their expression did not correlate with clinical outcomes. GM-CSF activated non-canonical signaling pathways in TCs, promoted their invasiveness and enhanced in vivo lung colonization in a murine model. GM-CSF–primed macrophages secreted higher levels of inflammatory cytokines upon interaction with melanoma cells than those unprimed or primed with M-CSF. Reciprocally, RNA-seq analyses revealed a broader transcriptional reprogramming in melanoma cells exposed to GM-CSF-primed macrophages.

Our findings highlight a potentially pro-tumorigenic GM-CSF-driven paracrine axis in patients with poor-prognosis melanoma, supporting therapeutic strategies aimed at disrupting this signaling network.