The immunogenomic features of tumor-adjacent lungs (TALs) in stage I lung squamous cell carcinoma (LUSC) aren't clear. Multiomics analyses of tumor tissues and paired TALs from 59 stage I LUSC patients were performed. Compared to tumors, TALs exhibited a better preserved immune contexture indicated by upregulation of immune pathways, increased immune infiltration and higher expression of immune effector molecules. Notably, TALs had no mutations in PTEN and KEAP1, a lower incidence of human

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... cyte antigen (HLA) loss and higher expression of HLA class I genes, MHC I chaperones and IFN-γ-associated genes. Digital spatial profiling validated the generally higher immune infiltration in TALs and revealed a higher level of immune heterogeneity in LUSC tumors. Importantly, patients with higher immune infiltration in TALs had significantly longer survival, while high immune heterogeneity was associated with inferior patient survival. Our work can be considered in the selection of patients for adjuvant therapy, especially immunotherapy.