biostudies-literatureValencia KEuropean Social FundInstituto de Salud Carlos IIIFundación Ramón ArecesFundación para la investigación médica aplicadaContratos Predoctorales de Formación en Investigación en SaludFundación Roberto Arnal PlanellesMinistry of EconomyInternational Association for the Study of Lung CancerSpanish Association Against Cancer Scientific FoundationCentro de Investigación Biomédica en Red de CáncerEuropean Regional Development Funde20220726https://www.ebi.ac.uk/biostudies/studies/S-EPMC9524203biostudies-literatureUnknown219(12)Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment.The Journal of experimental medicineDSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity.PMC9524203PI19/00098PI19/00230CB16/12/00443FI20/00295PI20/00419GCB14-2170Montuenga LMPicabea BMelero IAmat RFelip ESainz CTamayo IEchepare MBosco GBertolo CThomas RAgorreta JPasquier ALopez-Picazo JMFrigola JCalvo ATeijeira AValencia KfalseDSTYK inhibition increases the sensitivity of lung cancer cells to T cell-mediated cytotoxicity.Lung cancer remains the leading cause of cancer-related death worldwide. We identify DSTYK, a dual serine/threonine and tyrosine non-receptor protein kinase, as a novel actionable target altered in non-small cell lung cancer (NSCLC). We also show DSTYK's association with a lower overall survival (OS) and poorer progression-free survival (PFS) in multiple patient cohorts. Abrogation of DSTYK in lung cancer experimental systems prevents mTOR-dependent cytoprotective autophagy, impairs lysosomal biogenesis and maturation, and induces accumulation of autophagosomes. Moreover, DSTYK inhibition severely affects mitochondrial fitness. We demonstrate in vivo that inhibition of DSTYK sensitizes lung cancer cells to TNF-α-mediated CD8+-killing and immune-resistant lung tumors to anti-PD-1 treatment.2022-01-01T00:00:00Z2022 Dec2026-07-14T21:05:42.323Z2025-04-04T20:21:18.968ZS-EPMC95242033616965210.1084/jem.20220726