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In lung adenocarcinoma (LUAD), the appearance of morphologically diverse tumor regions, termed histological patterns, is closely associated with disease progression and lymph node metastasis. However, the molecular characteristics of the histological patterns in LUAD and the underlying molecular evolutionary mechanisms between the histological patterns in primary tumors and lymph node metastases are poorly understood. Here, we re-analyzed the large TCGA-LUAD dataset and depicted a comprehensive profiling of the genome and transcriptome across the histological patterns in LUAD. Tumor phylogenetic trajectory analysis suggested that the complex glands is more apt to metastasize to the lymph node. Further deconvolution of the tumor microenvironment demonstrated that the complex glands had a higher infiltration of cancer-associated fibroblasts (CAFs). Single-cell transcriptome profiling of complex glands pattern identified a novel CAF subtype co-expressing fibroblast activation protein-alpha (FAP) and stimulator of interferon genes (STING). Moreover, our data demonstrated that FAP is an important downstream effector of STING in CAFs. In summary, our results provide the basis for the development of innovative therapeutic guidelines and intervention strategies for LUAD patients., (© 2022 John Wiley & Sons Ltd.)