Summary Non-melanoma skin cancer, the most common US tumor, encompasses basal cell (BCC) and squamous cell (SCC) carcinomas, and leads to extensive morbidity and mortality. ARO46786 now in its 20th year, has focused on BCC-to-SCC transition (BST) a common but understudied resistance mechanism that represents a significant challenge to therapy and poorer outcomes. We propose five major BST Keratocarcinoma (KC) cell states and show that combinatorial AP-1 and SRF co-factor interactions provide the transcriptional switch from HH sensitivity to RAS-MAPK dependence and that c-FOS-driven BST appears reversible. By contrast, interrogation of stromal heterogeneity identified a skin cancer-associated macrophage (SCAM) required for BCC growth in allografts and organoids. SCAMs are self-propagating, transplantable, and long-lived in the BCC tumor environment. Tumor- associated macrophages have been shown to have proliferative and anti-immune checkpoint activity highlighting the gap in knowledge about the skin microenvironment. These preliminary studies support our overarching hypothesis that BST and SCAMs mediate BCC tumor evolution and resistance. To further test this hypothesis, ARO46786 will: Elucidate the drivers and sensitivities of BST by refining the KC chromatin and tumor dependency map and elucidating the mechanism of the reversible BST transcription factor switch; and elucidate the origin and function of SCAMs in BCC growth by dissecting SCAM function on tumor epithelial growth and identifying the determinants of SCAM polarization and function. Project completion will fill major gaps in our understanding how the tumor epithelium and microenvironment contribute to resistance, and lead to the nomination of novel cancer therapies.