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

Abstract

IntroductionCancer 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.MethodsHere, 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.ResultsWe 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.DiscussionTogether, 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.

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BibTeX RIS

BibTeX

@article{shirley2026sting,
  title = {{STING signaling opposes AXL to regulate interferon responses in dedifferentiated human melanoma}},
  author = {Carl A. Shirley and Michael B. Wolfe and Karla B. Anaya-Aldrete and Minakshi Nihal and Gagan Chhabra and Sean J. McIlwain and Julia M. Krien and Mary A. Ndiaye and Nihal Ahmad},
  journal = {Frontiers in Oncology},
  year = {2026},
  month = nov,
  doi = {10.3389/fonc.2026.1946947},
  url = {https://www.frontiersin.org/articles/10.3389/fonc.2026.1946947},
  note = {CC BY 4.0},
}

RIS

TY  - JOUR
TI  - STING signaling opposes AXL to regulate interferon responses in dedifferentiated human melanoma
AU  - Carl A. Shirley
AU  - Michael B. Wolfe
AU  - Karla B. Anaya-Aldrete
AU  - Minakshi Nihal
AU  - Gagan Chhabra
AU  - Sean J. McIlwain
AU  - Julia M. Krien
AU  - Mary A. Ndiaye
AU  - Nihal Ahmad
PY  - 2026
DA  - 2026/11/05
JO  - Frontiers in Oncology
DO  - 10.3389/fonc.2026.1946947
UR  - https://www.frontiersin.org/articles/10.3389/fonc.2026.1946947
AB  - IntroductionCancer 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.MethodsHere, 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.ResultsWe 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.DiscussionTogether, 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.
SN  - 2234-943X
ER  -

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