This study presents a comprehensive single-cell and spatial transcriptomics analysis of non-small cell lung cancer (NSCLC) in 25 treatment-naive patients with adenocarcinoma (LUAD) and squamous-cell carcinoma (LUSC). Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the researchers identified 895,806 high-quality cells, revealing significant differences in immune and non-immune cell composition between tumour and adjacent non-tumour tissue. They found that tumours exhibited a higher diversity of immune and non-immune cells compared to adjacent tissue, with notable differences in the co-expression of immune checkpoint inhibitors (ICIs) between LUAD and LUSC. The study also revealed evidence of a transcriptional "reprogramming" of macrophages in tumours, shifting them towards cholesterol export and adopting a foetal-like transcriptional signature that promotes iron efflux. The researchers identified distinct cell types, including cancer-associated macrophage-like cells (CAMLs), which showed a strong correlation with therapeutic response. They found that LUAD and LUSC had similar cellular compositions but utilized different cell-cell interaction networks. The study highlighted the importance of understanding the tumour microenvironment (TME) and the complexity of cell-cell interactions within it. The integration of scRNA-seq and spatial transcriptomics data confirmed the spatial co-localization of key ligand-receptor pairs, providing insights into the interactions between different cell types in the TME. The study also revealed that tumour-associated macrophages (TAMs) exhibited a transcriptional signature reminiscent of macrophages during foetal lung development, suggesting oncofoetal reprogramming. This reprogramming was associated with increased cholesterol and iron efflux, which may support tumour progression. The findings underscore the importance of understanding the dynamic relationship between lung cancer and macrophages to develop more effective therapeutic strategies. The study provides a high-resolution molecular map of tumour-associated macrophages, enhancing our understanding of their role within the tumour microenvironment.This study presents a comprehensive single-cell and spatial transcriptomics analysis of non-small cell lung cancer (NSCLC) in 25 treatment-naive patients with adenocarcinoma (LUAD) and squamous-cell carcinoma (LUSC). Using single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics, the researchers identified 895,806 high-quality cells, revealing significant differences in immune and non-immune cell composition between tumour and adjacent non-tumour tissue. They found that tumours exhibited a higher diversity of immune and non-immune cells compared to adjacent tissue, with notable differences in the co-expression of immune checkpoint inhibitors (ICIs) between LUAD and LUSC. The study also revealed evidence of a transcriptional "reprogramming" of macrophages in tumours, shifting them towards cholesterol export and adopting a foetal-like transcriptional signature that promotes iron efflux. The researchers identified distinct cell types, including cancer-associated macrophage-like cells (CAMLs), which showed a strong correlation with therapeutic response. They found that LUAD and LUSC had similar cellular compositions but utilized different cell-cell interaction networks. The study highlighted the importance of understanding the tumour microenvironment (TME) and the complexity of cell-cell interactions within it. The integration of scRNA-seq and spatial transcriptomics data confirmed the spatial co-localization of key ligand-receptor pairs, providing insights into the interactions between different cell types in the TME. The study also revealed that tumour-associated macrophages (TAMs) exhibited a transcriptional signature reminiscent of macrophages during foetal lung development, suggesting oncofoetal reprogramming. This reprogramming was associated with increased cholesterol and iron efflux, which may support tumour progression. The findings underscore the importance of understanding the dynamic relationship between lung cancer and macrophages to develop more effective therapeutic strategies. The study provides a high-resolution molecular map of tumour-associated macrophages, enhancing our understanding of their role within the tumour microenvironment.