biostudies-literatureBarnet MBBioplatforms Australia (Bioplatforms)Bill and Patricia Ritchie FoundationNHMRCKinghorn Foundation (The Kinghorn Foundation)e2314258122https://www.ebi.ac.uk/biostudies/studies/S-EPMC12280981biostudies-literatureUnknown122(28)Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients. Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes. Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, <i>NOD2</i>, in an exceptional immune responder to targeted radiotherapy for metastatic melanoma. In 40 exceptional immune responders to anti-PD1 monotherapy for non-small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a <i>NOD2</i> LOF variant, more than twice the population frequency (<i>P</i> = 0.0021). CoProceedings of the National Academy of Sciences of the United States of AmericaCommon inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy.PMC12280981no grant numberAPP2010134Mawson AZhang FGao BPeters GWright KKhan ZJara CJBurnett DLHold GLJohn TPeters TJCooper WAKao SCBruce JMasle-Farquhar EJackson KJLBoyer MDavis IDBarnet MBCebon JFaulks MPugh TRussell AHui RGoodnow CCHeller GBehren AJoshua AMYang CBlinman PLAllen IChye ABrink RJunankar SNagrial AProkopec SfalseCommon inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy.Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients. Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes. Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, <i>NOD2</i>, in an exceptional immune responder to targeted radiotherapy for metastatic melanoma. In 40 exceptional immune responders to anti-PD1 monotherapy for non-small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a <i>NOD2</i> LOF variant, more than twice the population frequency (<i>P</i> = 0.0021). Co2025-01-01T00:00:00Z2025 Jul2026-03-27T15:26:00.539Z2025-08-23T03:09:29.057ZS-EPMC122809814062317710.1073/pnas.2314258122