Lung adenosquamous carcinoma (LASC) is distinct from lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC), exhibiting higher malignancy and poorer prognosis. However, there is limited understanding of its single-cell heterogeneity, particularly in comparison to the single-cell heterogeneity of LUAD and LUSC. Here, we analyzed single-cell transcriptomic data from 34 tissue biopsy samples derived from 8 LUAD, 6 LASC, and 6 LUSC patients, and first present a single-cell resolution atlas for these distinct non-small cell lung cancer subtypes. We found that LUSC fibroblasts had higher heterogeneity compared with those from LUAD and LASC. Insulin-like growth factor binding protein 2-positive (IGFBP2+) fibroblasts exhibited the strongest interactions with macrophages, particularly a synergistic interaction with secreted phosphoprotein 1-positive (SPP1+) macrophages. Spatial relationship and crosstalk of these two subtypes were validated using independent datasets and in vivo experiments. Our findings offer a novel perspective on the biological mechanisms of tumor microenvironment in adeno-to-squamous transition, offering potential targets for therapeutic strategies in managing this disease progression.