Single-cell multimodal profiling of pan-cancer cell lines uncovers gene regulatory principles underlying intrinsic cell states and environmental features

Cancer arises from somatic mutations whose effects are executed through dysregulated gene-regulatory programs that reshape chromatin, transcription, and malignant phenotypes. To uncover gene regulatory principles underlying heterogeneous cancer cell states and their linked environmental features, here we present a pan-cancer single-cell, multi-omic atlas of human cancer cell lines, including a compendium of 240,957 transcriptomes and 223,347 chromatin-accessibility profiles from primary cancers spanning 20 tumor types. We revealed extensive pan-cancer cell-state heterogeneity, core gene-regulatory networks, and consensus epithelial–mesenchymal transition (EMT) trajectories that transcend tissue of origin and are governed by conserved epigenomic and transcriptomic features. In addition, our copy-number variation analysis implicated transcription factor amplification, followed by hyperactive downstream regulation, as a major driver of malignant states. Further focused analysis of acral versus cutaneous melanoma cell lines uncovers a universal inflammation-suppressive program in acral melanoma versus an inflamed regulatory landscape in cutaneous melanoma, highlighting the JAK–STAT axis as a key discriminator. Finally, by integrating single-cell and bulk datasets across models and patient cohorts, we revealed tumor–microenvironment co-adaptation in vivo, and this was associated with immunotherapy responsiveness.