Our data identified (i) a unique cellular atlas of healthy lungs and EGFRTL-driven adenocarcinomas (ADC), by resolving distinct epithelial and TME clusters/subpopulations of immune, endothelial, and fibroblast nature; (ii) new cell subtypes that are distinguishingly associated with EGFR-driven lung tumors, highlighting differences between tumor and healthy tissue; (iii) a comprehensive single cell–based ecosystem of cell-cell communications contributing to mold the aggressive ADC environment. This evidence concerns the gene EGFR and neoplasm.