Molecular phenotypes and spatial archetypes: A new framework for cancer-associated fibroblasts

Cancer-associated fibroblasts (CAFs) form a dynamic ecosystem that critically influences tumor progression and therapeutic response. Although recent advances in single-cell and spatial omics have uncovered profound stromal diversity, interpreting the mechanistic relevance of this complexity remains a challenge. Here, we propose a more unifying conceptual framework to bridge high-dimensional data with experimental biology. By categorizing CAFs into conserved molecular phenotypes and distinct spatial archetypes, this model illustrates how CAF identities are intimately linked to local tissue contexts. This refined framework brings the complexity of the tumor stroma into greater focus, underscoring the necessary transition from broad stromal targeting toward precision, context-specific modulation. Ultimately, we hope this integrated effort will aid in the collaborative development of next-generation therapies that selectively target pathogenic stroma in cancer to improve patient outcomes.