Work

STING signaling opposes AXL to regulate interferon responses in dedifferentiated human melanoma

Year: 2026

Type: article

Abstract: Introduction Cancer cells can evade interferon (IFN) signaling pressures by suppressing intrinsic innate immune signaling pathways or dedifferentiating, giving rise to immunotherapy-resistant cell states. Therapeutic strategies specifically tailored to account for and eliminate such states remain limited. Methods Here, we genetically reintroduced stimulator of interferon genes (STING) in dedifferentiated STING-deficient melanoma cells, used AXL receptor tyrosine kinase (AXL) small-molecule inhibition, and analyzed publicly available single-cell RNA-sequencing (scRNA-seq) datasets to examine connections between dedifferentiation and interferon responses in human melanoma. Results We found that STING reintroduction induced type I IFN signaling, increased expression of antigen-presentation genes, and enhanced sensitivity to exogenous type II IFN. STING signaling silenced expression of AXL, a key marker of melanoma dedifferentiation. AXL small-molecule inhibition partially phenocopied STING reintroduction, potentiating antigen-presentation gene expression and enhancing type II IFN sensitivity in dedifferentiated human melanoma cells. Consistently, analysis of publicly available human melanoma scRNA-Seq data revealed tumor cells with concomitant STING loss and AXL gain are positively enriched for melanocyte stem-cell-like signatures, while negatively enriched for interferon and immune activation signatures. Discussion Together, through manipulation of human melanoma cell lines and analysis of single-cell states, our results support opposing roles for STING and AXL in the regulation of antigen-presenting genes and interferon sensitivity and more broadly implicate changes to interferon sensitivity in the dedifferentiation process.

Source: Frontiers in Oncology

DOI: 10.3389/fonc.2026.1946947