Ryan H. Boe, Catherine G. Triandafillou, Rossana Lazcano, Jennifer A. Wargo, Arjun Raj
Abstract Resistance to cancer therapy is driven by both cell-intrinsic and microenvironmental factors. We use spatial transcriptomics and single-cell RNA sequencing to uncover distinct resistance programs in melanoma cells shaped by intrinsic cellular states and the tumor microenvironment. Consensus non-negative matrix factorization reveals shared intrinsic resistance programs across cell lines. In patient samples, these resistance programs coexist within individual tumors and associate with diverse immune signatures. Single-cell resolution spatial transcriptomics in xenograft models reveals both intrinsically determined and extrinsically influenced resistant fates. This work demonstrates that therapy-resistant fates coexist within distinct microenvironments and that tissue features influence which fate is adopted.