Abstract
TP53 is the most frequently mutated gene across many cancers and is associated with shorter survival in lung adenocarcinoma (LUAD). To define how TP53 mutations affect the LUAD tumor microenvironment (TME), we constructed a multi-omic cellular and spatial tumor atlas of 23 treatment-naïve human lung tumors. We found that TP53 -mutant ( TP53 (mut) ) malignant cells lose alveolar identity and upregulate highly proliferative and entropic gene expression programs consistently across resectable LUAD patient tumors, genetically engineered mouse models, and cell lines harboring a wide spectrum of TP53 mutations. We further identified a multicellular tumor niche composed of SPP1 (+) macrophages and collagen-expressing fibroblasts that coincides with hypoxic, pro-metastatic expression programs in TP53 (mut) tumors. Spatially correlated angiostatic and immune checkpoint interactions, including CD274 - PDCD1 and PVR - TIGIT , are also enriched in TP53 (mut) LUAD tumors, which may influence response to checkpoint blockade therapy. Our methodology can be further applied to investigate mutation-specific TME changes in other cancers.