Abstract

Lung adenocarcinoma (LUAD) harboring distinct actionable oncogenic mutations exhibits differential responses to immune checkpoint inhibitors (ICI); however, the underlying mechanisms remain elusive. Here, we report comprehensive single-cell spatial atlases of tumors from 38 LUAD patients, predominantly harboring rare actionable oncogenes. Stratifying patients by consensus meta-programs (MP) reveals ICI-MP-H (high) and ICI-MP-L (low) subgroups. The ICI-MP-H group exhibits significant enrichment of the E3-IFI6 epithelial subpopulation, which displays high expression of interferon- and antigen presentation-related genes. Spatially, E3-IFI6 is adjacent to the Ma-MHC myeloid subpopulation; both co-enrich in a specific niche and likely interact via the APP-CD74 axis. Functional assays confirm that IFI6 overexpression in LUAD cell lines promotes proinflammatory macrophage activation. Our study systematically characterizes the features of the tumor ecosystem for different driver oncogene mutations, providing a theoretical basis for future clinical implementation of ICI therapy in patients with LUAD carrying rare mutations.