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In contrast, myeloid cells massively infiltrate tumors and are well adapted to survive these harsh conditions. While they are equipped with cell-killing abilities, they often adopt an immunosuppressive phenotype upon migration to tumors. Therefore, the questions of how to modify their activation programming against cancer, and what signaling cascades should be activated in myeloid cells to elicit their cytotoxicity have remained unclear. Here, we found that activation of IgM-induced signaling in murine myeloid cells results in secretion of lytic granules and massive tumor cell death. These findings open venues for designing novel immunotherapy by equipping monocytes with chimeric receptors that target tumor antigens and consequently, signal through IgM receptor. Nonetheless, we found that myeloid cells do not express the antibody-derived portion used to recognize the tumor antigen due to the induction of an ER stress response. To overcome this limitation, we designed chimeric receptors that are based on the high-affinity Fc\u03b3RI for IgG. Incubation of macrophages expressing these receptors along with tumor-binding IgG induced massive tumor cell killing and secretion of reactive oxygen species and Granzyme B. Overall, this work highlights the challenges involved in genetically reprogramming the signaling in myeloid cells and provides a framework for endowing myeloid cells with antigen-specific cytotoxicity.<\/jats:p>","DOI":"10.7554\/elife.91999","type":"journal-article","created":{"date-parts":[[2023,12,27]],"date-time":"2023-12-27T08:54:38Z","timestamp":1703667278000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.91999","source":"Crossref","is-referenced-by-count":2,"title":["Expression of modified Fc\u03b3RI enables myeloid cells to elicit robust tumor-specific cytotoxicity"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8622-6788","authenticated-orcid":true,"given":"Leen","family":"Farhat-Younis","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/04mhzgx49","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Pathology, School of Medicine, Tel Aviv University","place":["Tel Aviv, 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