biostudies-literatureVicencio JMCancer Research Institute/Wade FB Thompson CLIP Reference Number CRI3645Cancer Research UKAstraZenecaEU IMI2 IMMUCAN274https://www.ebi.ac.uk/biostudies/studies/S-EPMC8960767biostudies-literatureUnknown13(3)Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. OsimertCell death & diseaseOsimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.PMC8960767C604/A27442C1519/A27375C604/A25135C1519/A28682C7675/A2931317688510029191C1519/A16463DCRPGF\100009C7893/A26233Capone EHochhauser DYarden YClancy JLawler KGomes CParsons MArnold JNDeng JAlfano GChan JNEWeitsman GVicencio JMCoban OGordon PQuezada SADe-Souza KIacobelli SWong FHartley JAEvans RAn ZDolcetti LTreacy CBarber PRChalk AAmeer-Beg SNg KSala GGomez VPan TSosnowska DNg TMonypenny JCostoya CGreen RMustapha RSavage CChen SHFlores-Borja FfalseOsimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans.Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimert2022-01-01T00:00:00Z2022 Mar2025-04-21T17:31:40.238Z2025-04-05T16:40:39.888ZS-EPMC89607673534710810.1038/s41419-022-04701-3