ArticleMolecular cancer research : MCR2023
Targeting ULK1 Decreases IFNγ-Mediated Resistance to Immune Checkpoint Inhibitors.
Article in Molecular cancer research : MCR, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 16 citations in OpenAlex.
- Article
- Schlafen 5 is an intracellular immune checkpoint and controls IFN responses in pancreatic ductal adenocarcinoma.JCI insight · 2026Article
- Ferroptosis, pyroptosis, and necroptosis in melanoma: regulatory cell death pathways and their implications for immunotherapy.Frontiers in oncology · 2026Review
- Autophagy and mitophagy in dermatological disease: a comprehensive review from molecular pathways to therapeutic frontiers.Biology direct · 2025Review
- [Machine learning-based programmed cell death signature model for precise prediction of prognosis and treatment response in melanoma].Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences · 2025Article
- Identification of a Treg-related gene signature for predicting prognosis and immunosuppression in skin cutaneous melanoma.Clinical and experimental medicine · 2025Article
- Balancing between cuproplasia and copper-dependent cell death: molecular basis and clinical implications of ATOX1 in cancer.Journal of experimental & clinical cancer research : CR · 2025Review
- Dual role of interferon-gamma in the response of melanoma patients to immunotherapy with immune checkpoint inhibitors.Molecular cancer · 2025Review
- PD-1 blockade treatment in melanoma: Mechanism of response and tumor-intrinsic resistance.Cancer science · 2025Review
- Loss of Function Mouse Models Reveal a Novel Regulatory Function for ULK1 in Myeloproliferative Neoplasms.Molecular and cellular biology · 2025Article
- Physiological functions of ULK1/2.Journal of molecular biology · 2024Review
- Diapause-like Drug-Tolerant Persister State: The Key to Nirvana Rebirth.Medicina (Kaunas, Lithuania) · 2024Review
- Immune Assessment Today: Optimizing and Standardizing Efforts to Monitor Immune Responses in Cancer and Beyond.Cancers · 2024Article
- Review
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Authors and funding
13 authors at 3 institutions in 1 country.
Funding
Abstract
Immune checkpoint inhibitors (ICI) have transformed the treatment of melanoma. However, the majority of patients have primary or acquired resistance to ICIs, limiting durable responses and patient survival. IFNγ signaling and the expression of IFNγ-stimulated genes correlate with either response or resistance to ICIs, in a context-dependent manner. While IFNγ-inducible immunostimulatory genes are required for response to ICIs, chronic IFNγ signaling induces the expression of immunosuppressive genes, promoting resistance to these therapies. Here, we show that high levels of Unc-51 like kinase 1 (ULK1) correlate with poor survival in patients with melanoma and overexpression of ULK1 in melanoma cells enhances IFNγ-induced expression of immunosuppressive genes, with minimal effects on the expression of immunostimulatory genes. In contrast, genetic or pharmacologic inhibition of ULK1 reduces expression of IFNγ-induced immunosuppressive genes. ULK1 binds IRF1 in the nuclear compartment of melanoma cells, controlling its binding to the programmed death-ligand 1 promoter region. In addition, pharmacologic inhibition of ULK1 in combination with anti-programmed cell death protein 1 therapy further reduces melanoma tumor growth in vivo. Our data suggest that targeting ULK1 represses IFNγ-dependent immunosuppression. These findings support the combination of ULK1 drug-targeted inhibition with ICIs for the treatment of patients with melanoma to improve response rates and patient outcomes. IMPLICATIONS: This study identifies ULK1, activated downstream of IFNγ signaling, as a druggable target to overcome resistance mechanisms to ICI therapy in metastatic melanoma.
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