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As there is growing evidence for the tumor microenvironment's role in tumorigenesis, we investigated the role of fibroblast-expressed kinases in triple-negative breast cancer (TNBC). Using a high-throughput kinome screen combined with 3D invasion assays, we identified fibroblast-expressed PIK3C[delta] (f- PIK3C[delta]) as a key regulator of cancer progression. Although PIK3C[delta] was expressed in primary fibroblasts derived from TNBC patients, it was barely detectable in breast cancer (BC) cell lines. Genetic and pharmacological gain- and loss-of-function experiments verified the contribution of f-PIK3C[delta] in TNBC cell invasion. Integrated secretomics and transcriptomics analyses revealed a paracrine mechanism via which f-PIK3C[delta] confers its protumorigenic effects. Inhibition of f-PIK3C[delta] promoted the secretion of factors, including PLGF and BDNF, that led to upregulation of NR4A1 in TNBC cells, where it acts as a tumor suppressor. Inhibition of PIK3C[delta] in an orthotopic BC mouse model reduced tumor growth only after inoculation with fibroblasts, indicating a role of f-PIK3C[delta] in cancer progression. Similar results were observed in the MMTV-PyMT transgenic BC mouse model, along with a decrease in tumor metastasis, emphasizing the potential immune-independent effects of PIK3C[delta] inhibition. Finally, analysis of BC patient cohorts and TCGA data sets identified f-PIK3C[delta] (protein and mRNA levels) as an independent prognostic factor for overall and disease-free survival, highlighting it as a therapeutic target for TNBC., Introduction Triple-negative breast cancer (TNBC; [ER.sup.-], [PR.sup.-], [HER2.sup.-]) represents a molecularly diverse and highly heterogeneous subtype of breast cancer (BC) (15%-20%) with a poor prognosis and high rates of recurrence [...]