This study investigates the transcriptomic and spatial characteristics of non-small cell lung cancer (NSCLC) using single-cell and spatial transcriptomics. The researchers analyzed approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma. They found an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, with reduced NK cell cytotoxicity within the tumor. While both subtypes showed similar cell type compositions, significant differences were observed in the co-expression of various immune checkpoint inhibitors. The study also revealed a transcriptional "reprogramming" of macrophages in tumors, shifting them towards cholesterol export and adopting a fetal-like transcriptional signature that promotes iron efflux. The multi-omic resource provides a high-resolution molecular map of tumor-associated macrophages, enhancing understanding of their role in the tumor microenvironment. The findings suggest that specific immunotherapies targeting ICIs such as TIM3, TIGIT, and CD96 may benefit LUAD and LUSC patients. Additionally, the study highlights the importance of anti-inflammatory macrophages in modulating the tumor microenvironment and their potential role in tumor progression through sustained iron release.This study investigates the transcriptomic and spatial characteristics of non-small cell lung cancer (NSCLC) using single-cell and spatial transcriptomics. The researchers analyzed approximately 900,000 cells from 25 treatment-naive patients with adenocarcinoma and squamous-cell carcinoma. They found an inverse relationship between anti-inflammatory macrophages and NK cells/T cells, with reduced NK cell cytotoxicity within the tumor. While both subtypes showed similar cell type compositions, significant differences were observed in the co-expression of various immune checkpoint inhibitors. The study also revealed a transcriptional "reprogramming" of macrophages in tumors, shifting them towards cholesterol export and adopting a fetal-like transcriptional signature that promotes iron efflux. The multi-omic resource provides a high-resolution molecular map of tumor-associated macrophages, enhancing understanding of their role in the tumor microenvironment. The findings suggest that specific immunotherapies targeting ICIs such as TIM3, TIGIT, and CD96 may benefit LUAD and LUSC patients. Additionally, the study highlights the importance of anti-inflammatory macrophages in modulating the tumor microenvironment and their potential role in tumor progression through sustained iron release.