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

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.