2. Academic Validation
  3. Targeting the DSTYK-ULK1 axis rewires TNFR1 signaling to overcome treatment resistance in lung cancer

Targeting the DSTYK-ULK1 axis rewires TNFR1 signaling to overcome treatment resistance in lung cancer

  • Cell Rep. 2026 Mar 24;45(3):117087. doi: 10.1016/j.celrep.2026.117087.
Andrea Pasquier 1,  Cristina Viu-Idocin 2,  Andrea Arricibita 1,  Mirari Echepare 3,  Beñat Picabea 2,  Daniel Orive 3,  Ane Álava 2,  Joaquín Fernández-Irigoyen 4,  Enrique Santamaría 4,  Allan Argueta 5,  Eva Molina 6,  Antonio Pineda-Lucena 6,  Marco Gentili 7,  Federica Facchinetti 7,  Luca Roz 7,  Luis M Montuenga 3,  Karmele Valencia 8
Affiliations

Affiliations

  • 1 Program in Solid Tumors, Cancer Division, CIMA-University of Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain.
  • 2 Program in Solid Tumors, Cancer Division, CIMA-University of Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain.
  • 3 Program in Solid Tumors, Cancer Division, CIMA-University of Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain; Consorcio de Investigación Biomédica en Red de Cáncer (CIBERONC), 28040 Madrid, Spain; Navarra Health Research Institute (IDISNA), 31008 Pamplona, Spain; Department of Pathology, Anatomy and Physiology, Schools of Sciences and Medicine, University of Navarra, 31008 Pamplona, Spain.
  • 4 Navarra Health Research Institute (IDISNA), 31008 Pamplona, Spain; Clinical Neuroproteomics Unit, Proteomics Platform, Navarrabiomed, Hospital Universitario de Navarra (HUN), Public University of Navarra (UPNA), 31008 Pamplona, Spain.
  • 5 Department of Pathology, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
  • 6 Therapeutic Innovation Program, Enabling Technologies Division, CIMA-University of Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain.
  • 7 Tumor Genomics Unit, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy.
  • 8 Program in Solid Tumors, Cancer Division, CIMA-University of Navarra, Cancer Center Clínica Universidad de Navarra (CCUN), 31008 Pamplona, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, 31008 Pamplona, Spain; Consorcio de Investigación Biomédica en Red de Cáncer (CIBERONC), 28040 Madrid, Spain; Navarra Health Research Institute (IDISNA), 31008 Pamplona, Spain. Electronic address: [email protected].
PMID: 41824459 DOI: 10.1016/j.celrep.2026.117087
Abstract

Immunotherapy has transformed the treatment of non-small cell lung Cancer (NSCLC). Yet, acquired resistance remains a major clinical challenge. Defining molecular determinants of tumor sensitivity to T cell-mediated killing is therefore critical. Tumor necrosis factor α (TNF-α) released by cytotoxic T cells promotes tumor cell death, whereas NF-κB signaling supports survival. Autophagy counteracts TNFα-induced Apoptosis, and its inhibition enhances responses to immune checkpoint inhibitors (ICIs). Genomic alterations further contribute to immune evasion and reduced immunotherapy efficacy. We previously identified DSTYK, a dual serine/threonine and tyrosine kinase amplified in NSCLC, as a suppressor of TNF-α-mediated CD8+ T cell killing and a driver of ICI resistance through Autophagy. Here, we show that DSTYK modulates TNFR1 signaling by phosphorylating the Autophagy initiator ULK1, which enables ULK1-dependent phosphorylation of RIPK1. Loss of DSTYK disrupts ULK1 activation, promotes RIPK1 autophosphorylation, proapoptotic signaling, and impaired NF-κB-dependent survival. These findings define a DSTYK-ULK1-RIPK1 axis controlling TNF-α-induced Apoptosis and support targeting ULK1 to sensitize DSTYK-amplified NSCLC to T cell-mediated killing.

Keywords

CP: cancer; CP: immunology; DSTYK; RIPK1; TNFR1 pathway; ULK1; apoptosis; autophagy; lung cancer.

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