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Monoclonal antibodies, immunoconjugates, T-cell engaging antibodies and CART cells have been incorporated into routine treatment algorithms, resulting in improved response rates. Nevertheless, patients continue to relapse and the underlying mechanisms of resistance remain poorly understood. While Impaired death receptor signaling has been reported to mediate resistance to CART in acute lymphoblastic leukemia, this mechanism yet remains to be elucidated in context of novel immunotherapies for MM. Here, we describe impaired death receptor signaling as a novel mechanism of resistance to T-cell mediated immunotherapies in MM. This resistance seems exclusive to novel immunotherapies while sensitivity to conventional anti-tumor therapies being preserved in vitro. As a proof of concept, we present a confirmatory clinical case indicating that the <jats:italic>FADD\/BID<\/jats:italic> axis is required for meaningful responses to novel immunotherapies thus we report impaired death receptor signaling as a novel resistance mechanism to T-cell mediated immunotherapy in MM.<\/jats:p>","DOI":"10.1038\/s42003-023-05683-4","type":"journal-article","created":{"date-parts":[[2023,12,21]],"date-time":"2023-12-21T15:03:15Z","timestamp":1703170995000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Impaired FADD\/BID signaling mediates cross-resistance to immunotherapy in Multiple Myeloma"],"prefix":"10.1038","volume":"6","author":[{"given":"Umair","family":"Munawar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiang","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabrina","family":"Prommersberger","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Silvia","family":"Nerreter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cornelia","family":"Vogt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3644-9187","authenticated-orcid":false,"given":"Maximilian 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C.H. reports other support from MLL Munich Leukemia Laboratory. J.M.-L. reports personal fees and nonfinancial support from Janssen, Sanofi, BMS, Roche and Gilead. H.E. reports grants and other support from Janssen, BMS\/Celgene, Amgen, GSK, and Sanofi, as well as other support from Takeda and Novartis. L.R. reports personal fees from BMS, Janssen, Pfizer, Amgen, GSK, Sanofi and support from German Cancer Aid\u2014MSNZ. Other authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"1299"}}