A study published in Nature Communications reveals the spatial organization and plasticity of immunosuppressive fibroblasts in breast cancer. Researchers identified 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. These niches are influenced by cancer cells, which drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive ECM-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation. Breast cancer is a heterogeneous disease classified into three main subtypes: luminal (Lum), HER2, and triple-negative (TN). The tumor microenvironment (TME) plays a key role in tumor growth and progression, with cancer-associated fibroblasts (CAF) being one of the most abundant components. CAF heterogeneity is now well-recognized, with several CAF populations identified in human breast cancer, including myofibroblastic CAF-S1 and perivascular-like CAF-S4. Myofibroblastic CAF populations are pro-metastatic and associated with BC progression. FAP+ CAF have also been associated with an immunosuppressive environment in various tumor types. The study used single-cell trajectory inference, deconvolution of spatial transcriptomics data, and functional assays to generate a high-resolution integrated map of breast cancer, focusing on inflammatory and myofibroblastic FAP+ CAF clusters. The results show that cancer cells promote the differentiation of Detox-iCAF into Wound-myCAF and ECM-myCAF clusters through DPP4- and YAP1-dependent mechanisms. These findings highlight the crucial role of DPP4 and YAP1/TEAD in driving the emergence of ECM-myCAF from Detox-iCAF through two independent mechanisms, shedding light on the molecular interactions underlying cancer immune escape. The study also reveals the spatial organization of FAP+ CAF clusters in breast cancer, showing that Detox-iCAF and IL-iCAF clusters are predominantly detected in the peritumor conjunctive tissue, while ECM-myCAF is the most abundant stromal subpopulation detected in the tumor bed. The study further identifies 10 co-localization patterns within the niches, called EcoCellTypes, which represent cell types and states co-existing across BC patients within the same tumor area. These EcoCellTypes areA study published in Nature Communications reveals the spatial organization and plasticity of immunosuppressive fibroblasts in breast cancer. Researchers identified 10 spatially-organized FAP+ CAF-related cellular niches, called EcoCellTypes, which are differentially localized within tumors. These niches are influenced by cancer cells, which drive the transition of detoxification-associated iCAF (Detox-iCAF) towards immunosuppressive ECM-producing myCAF (ECM-myCAF) via a DPP4- and YAP-dependent mechanism. ECM-myCAF polarize TREM2+ macrophages, regulatory NK and T cells to induce immunosuppressive EcoCellTypes, while Detox-iCAF are associated with FOLR2+ macrophages in an immuno-protective EcoCellType. FAP+ CAF subpopulations accumulate differently according to the invasive BC status and predict invasive recurrence of ductal carcinoma in situ (DCIS), which could help in identifying low-risk DCIS patients eligible for therapeutic de-escalation. Breast cancer is a heterogeneous disease classified into three main subtypes: luminal (Lum), HER2, and triple-negative (TN). The tumor microenvironment (TME) plays a key role in tumor growth and progression, with cancer-associated fibroblasts (CAF) being one of the most abundant components. CAF heterogeneity is now well-recognized, with several CAF populations identified in human breast cancer, including myofibroblastic CAF-S1 and perivascular-like CAF-S4. Myofibroblastic CAF populations are pro-metastatic and associated with BC progression. FAP+ CAF have also been associated with an immunosuppressive environment in various tumor types. The study used single-cell trajectory inference, deconvolution of spatial transcriptomics data, and functional assays to generate a high-resolution integrated map of breast cancer, focusing on inflammatory and myofibroblastic FAP+ CAF clusters. The results show that cancer cells promote the differentiation of Detox-iCAF into Wound-myCAF and ECM-myCAF clusters through DPP4- and YAP1-dependent mechanisms. These findings highlight the crucial role of DPP4 and YAP1/TEAD in driving the emergence of ECM-myCAF from Detox-iCAF through two independent mechanisms, shedding light on the molecular interactions underlying cancer immune escape. The study also reveals the spatial organization of FAP+ CAF clusters in breast cancer, showing that Detox-iCAF and IL-iCAF clusters are predominantly detected in the peritumor conjunctive tissue, while ECM-myCAF is the most abundant stromal subpopulation detected in the tumor bed. The study further identifies 10 co-localization patterns within the niches, called EcoCellTypes, which represent cell types and states co-existing across BC patients within the same tumor area. These EcoCellTypes are