Abstract The tumor microenvironment (TME) shows heterogeneity within a tumor. An important element of the TME is cancer-associated fibroblasts (CAF). In this issue of Cancer Research, Bouchard and colleagues investigate the heterogeneity of CAFs from spatially different zones of lung adenocarcinoma resection specimens. Multiomics analysis revealed changes in the O-glycoproteome, unique to CAFs from the tumor edge, an effect reinforced by contact with cancer cells. This O-glycoprotein signature offers unique targeting perspectives that reciprocally affect cancer cell epithelial-to-mesenchymal plasticity, a key mechanism of cancer progression. Deeper understanding of the cancer-stimulating and cancer-inhibiting role of CAF subtypes will facilitate the development of CAF-directed therapeutic approaches. See related article by Bouchard et al., p. 648