We show that a wide spectrum of TP53 mutations can remodel the cancer intrinsic properties of lung adenocarcinoma in a consistent manner across primary tumors, cell lines, and genetically engineered mouse models. 

 By integrating single-cell and spatial transcriptomics data, we find that TP53 mutation remodels the lung adenocarcinoma tumor microenvironment, making it more amenable to checkpoint blockade therapy. 

Using a compendium of single-cell chromatin accessibility data, we show that most small cell lung cancers arise from airway basal cells, while rare atypical cases have a neuroendocrine cell of origin