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The impact of the tumour microenvironment on the fate of cancer cells after CTX remains poorly understood. Here, we show that paracrine signalling from CTX\u2010treated cancer cells to stromal fibroblasts can drive cancer cell recovery after cytotoxic drug withdrawal. Interferon \u03b21 (IFN\u03b21) secreted by cancer cells following treatment with high doses of CTX instigates the acquisition of an anti\u2010viral state in stromal fibroblasts. This state is associated with an expression pattern here referred to as interferon signature (IFNS), which encompasses several interferon\u2010stimulated genes (ISGs), including numerous pro\u2010inflammatory cytokine genes. This crosstalk is an important driver of the expansion of BC cells after CTX, and IFN\u03b21 blockade in tumour cells abrogated their fibroblast\u2010dependent recovery potential. Analysis of human breast carcinomas supported a link between CTX\u2010induced IFNS in tumour stroma and poor response to CTX treatment. First, IFN\u03b21 expression in human breast carcinomas was found to inversely correlate with recurrence free survival (RFS). Second, using laser capture microdissection data sets, we show a higher expression of IFNS in the stromal tumour compartment compared to the epithelial one and this signature was found to be more prominent in more aggressive subtypes of BC (basal\u2010like), pointing to a pro\u2010tumorigenic role of this signature. Moreover, IFNS was associated with higher recurrence rates and a worse outcome in BC patients. Our study unravels a novel form of paracrine communication between cancer cells and fibroblasts that ultimately results in CTX resistance. Targeting this axis has the potential to improve CTX outcomes in patients with BC.<\/jats:p>","DOI":"10.1002\/1878-0261.12905","type":"journal-article","created":{"date-parts":[[2021,1,21]],"date-time":"2021-01-21T14:02:42Z","timestamp":1611237762000},"page":"1308-1329","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["IFN\u03b21 secreted by breast cancer cells undergoing chemotherapy reprograms stromal fibroblasts to support tumour growth after treatment"],"prefix":"10.1002","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1261-7211","authenticated-orcid":false,"given":"Ana","family":"Maia","sequence":"first","affiliation":[{"name":"Division of Molecular Genome Analysis German Cancer Research Center (DKFZ) Heidelberg Germany"},{"name":"Faculty of Biosciences University of Heidelberg 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