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However, ICD is dampened when tumors acquire resistance, affecting immune recognition. KDEL receptors (KDELRs), through a retrograde Golgi\u2010to\u2010ER transport, prevent spontaneous secretion of KDEL proteins. We report that inhibition of a single KDELR in a minor fraction of tumor cells, primarily KDELR2, provokes robust infiltration of macrophages and neutrophils into the tumor microenvironment, resulting in regression of both immunogenic and non\u2010immunogenic tumors initially independently of T cells. Importantly, in the course of regression, anti\u2010tumor T cells are primed, conferring protection against a second challenge. Recapitulated by intratumoral delivery of siDKELR2 utilizing lipid nanoparticles, we implicate KDELR2 as a target to unleash an unusual robust innate immune response, which represents a tractable approach to initiate an adaptive response downstream, bypassing conventional ICD\u2010inducing therapies. We propose KDELR targeting as a strategy to improve immunotherapy across tumor types, including \u201ccold\u201d tumors resistant to T cell\u2010based immunotherapies.<\/jats:p>","DOI":"10.1002\/advs.76148","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T19:35:01Z","timestamp":1782243301000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Inhibition of KDEL Receptors Remodels the Tumor Microenvironment for T Cell Independent Tumor Regression"],"prefix":"10.1002","volume":"13","author":[{"given":"Shakti P","family":"Pattanayak","sequence":"first","affiliation":[{"name":"Department of Biochemistry Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda","family":"Willard","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Shared Laboratory Resource Lerner Research Institute, Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy A.","family":"Chan","sequence":"additional","affiliation":[{"name":"Center for Immunotherapy and Precision Immuno\u2010Oncology Cleveland Clinic  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C","family":"Merrick","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng\u2010Rong","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Boaz","family":"Tirosh","sequence":"additional","affiliation":[{"name":"Department of Biochemistry Case Western Reserve University School of Medicine  Cleveland Ohio USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2023.09.011"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2019.1637188"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cej.2022.138781"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsnano.1c09048"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.200208083"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.4161\/onci.27878"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/smtd.202201083"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1186\/s43556\u2010022\u201000086\u2010z"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00204\u2010024\u201003681\u2010x"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.4161\/21624011.2014.955691"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010020\u201019970\u20109"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1080\/2162402X.2020.1792037"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586\u2010023\u201005912\u20100"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.194.6.781"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.250100"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2018.10.055"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M200425200"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature05768"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1089\/ars.2024.0558"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.abb.2016.11.007"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines10061234"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598\u2010024\u201065425\u20102"},{"issue":"9","key":"e_1_2_9_24_1","first-page":"2434","article-title":"Tumor Induction Relationships in Development of Transplantable Cancers of the Colon in Mice for Chemotherapy Assays, With a Note on Carcinogen Structure","volume":"35","author":"Corbett T. 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