Ryan H Boe, Catherine G Triandafillou, Rossana Lazcano, Jennifer A Wargo, Arjun Raj. Spatial transcriptomics reveals influence of microenvironment on intrinsic fates in melanoma therapy resistance. Genome Biol. 2026 May 23. doi: 10.1186/s13059-026-04112-z. Epub ahead of print. PMID: 42174697

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.