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While antibodies that activate Death Receptor 5 (DR5) were thought to have utility in the treatment of cancer by enhancing extrinsic apoptosis signaling, to date all clinical studies with these DR5 agonists have failed to deliver significant clinical benefit. A notable example of this is the DR5 agonistic antibody conatumumab. Here, we provide two potential avenues to improve the activity of DR5 agonists. First, we show that a dimeric IgA version (dIgA2) of the conatumumab antibody has a higher toxicity to cancer cells and a shorter half\u2010life\n                    <jats:italic>in vivo<\/jats:italic>\n                    compared to the original IgG version of the antibody. Moreover, we conducted a genome\u2010wide CRISPR screen to identify genes for which inactivation enhances the sensitivity of cancer cells to the dIgA2 DR5 antibody. We found that inhibition of mitochondrial protein translation synergizes with DR5 agonists. Consequently, antibiotics that inhibit mitochondrial protein translation also synergize with DR5 agonists. Finally, we show that these antibiotics activate the Integrated Stress Response (ISR) and upregulate DR5 through the EIF2a\u2010ATF4 axis, which sensitizes cancer cells to DR5 activation. These data suggest a potential combination strategy for the effective use of DR5 agonistic antibodies.\n                  <\/jats:p>","DOI":"10.1111\/febs.70669","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T05:06:12Z","timestamp":1785387972000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of mitochondrial protein translation sensitizes tumor cells to death receptor 5 agonistic antibody"],"prefix":"10.1111","author":[{"given":"Gabriele","family":"Casagrande Raffi","sequence":"first","affiliation":[{"name":"Division of Molecular Carcinogenesis, Oncode Institute The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oncology in South China Sun Yat\u2010sen University Cancer Center  Guangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsemieke","family":"Passchier","sequence":"additional","affiliation":[{"name":"Center for Translational Immunology University Medical Center Utrecht  Utrecht The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cor","family":"Lieftink","sequence":"additional","affiliation":[{"name":"Division of Molecular Carcinogenesis, NKI Robotic and Screening Center The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chrysa","family":"Papagianni","sequence":"additional","affiliation":[{"name":"Division of Molecular Carcinogenesis, Oncode Institute The Netherlands Cancer Institute  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeanette H. 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