{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T14:01:59Z","timestamp":1782741719740,"version":"3.54.5"},"reference-count":25,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T00:00:00Z","timestamp":1782691200000},"content-version":"unspecified","delay-in-days":28,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000090","name":"CDMRP","doi-asserted-by":"crossref","award":["BCRP W81XWH-22-1-1036"],"award-info":[{"award-number":["BCRP W81XWH-22-1-1036"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000090","name":"CDMRP","doi-asserted-by":"crossref","award":["HT94252410150"],"award-info":[{"award-number":["HT94252410150"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000090","name":"CDMRP","doi-asserted-by":"crossref","award":["HT94252410850"],"award-info":[{"award-number":["HT94252410850"]}],"id":[{"id":"10.13039\/100000090","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100007921","name":"University of Pittsburgh","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007921","id-type":"DOI","asserted-by":"publisher"}]},{"name":"PD30 Cancer Center Support"},{"DOI":"10.13039\/100015938","name":"Hillman Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015938","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100016645","name":"Shear Family Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100016645","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2026,3,13]]},"published-print":{"date-parts":[[2026,6]]},"abstract":"<jats:p>\n                    Why are clonal neoantigens paradoxically rare in established tumors? Why does tumor-associated antigen (TAA) burden inversely correlate with T-cell infiltration? Why do damage-associated molecular pattern (DAMP)\/danger signal-inducing interventions (messenger RNA (mRNA) vaccines, stereotactic body radiotherapy (SBRT), immunogenic chemotherapy) enhance checkpoint blockade activity in \u201ccold\u201d tumors? We propose the \u201cDEA Hypothesis\u201d to resolve these paradoxes: durable antitumor immunity for established tumors requires three convergent signals\u2014(1)\n                    <jats:bold>D<\/jats:bold>\n                    isinhibition of T cells through checkpoint blockade, (2)\n                    <jats:bold>E<\/jats:bold>\n                    nhanced recognition via the presentation of clonal neoantigens, and crucially, (3)\n                    <jats:bold>A<\/jats:bold>\n                    lerting the host through release of DAMPs\/danger signal(s). We frame cancer as a subversion of an ancient \u201cGuardian\u201d system\u2014the emergency hematopoietic response that evolved to orchestrate immune defense following epithelial breach or major trauma. Tumors hijack this system by promoting restorative hematopoiesis at the expense of immunity and masquerading as chronic wounds. This framework explains key observations: the paucity of clonal neoantigens reflects successful immunoediting over years of tumor evolution, not failed presentation. TAAs persist in cold tumors because insufficient DAMPs limit the \u201cDecision to Attack\u201d; and mRNA vaccines, recently SBRT, and immunogenic chemotherapy succeed in cold tumors by providing the missing Alert. For cold tumors, rational immunotherapy must extend beyond checkpoint blockade to reconstitute the Alert signal\u2014not merely releasing the brakes but providing the ignition to reawaken the ancient Guardian.\n                  <\/jats:p>\n                  <jats:p>Graphic abstract: The DEA hypothesis proposes that effective cancer immunotherapy requires three convergent signals: Disinhibition (checkpoint blockade), Enhanced recognition (clonal neoantigens), and Alerting the host (DAMP release). Panel I depicts immune decision points in tumor-draining lymph nodes. Panel II shows mutation-driven DAMP generation via the Poly(ADP-Ribose) Polymerase 1 - High Mobility Group Box 1 (PARP1-HMGB1) axis. Panel III illustrates the three-signal model converging on type 1 conventional dendritic cells activation. Panel IV demonstrates how immunoediting shapes stage-specific therapeutic strategies for cold, warm, and hot tumors.<\/jats:p>","DOI":"10.1136\/jitc-2026-015150","type":"journal-article","created":{"date-parts":[[2026,6,29]],"date-time":"2026-06-29T13:30:54Z","timestamp":1782739854000},"page":"e015150","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["DEA hypothesis: disinhibition, enhancing recognition, and alerting the host are the three pillars of effective cancer immunotherapy"],"prefix":"10.1136","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2570-7139","authenticated-orcid":false,"given":"Xiao-Song","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Pathology, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3988-5419","authenticated-orcid":false,"given":"Michael T","family":"Lotze","sequence":"additional","affiliation":[{"name":"Departments of Surgery, Immunology, and Bioengineering, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2026,6,29]]},"reference":[{"key":"2026062906301063000_14.6.e015150.1","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.85647","article-title":"TLR7 activation at epithelial barriers promotes emergency myelopoiesis and lung antiviral immunity","volume":"12","author":"Jackson","year":"2023","journal-title":"Elife"},{"key":"2026062906301063000_14.6.e015150.2","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2014.00197","article-title":"Does the immune system naturally protect against cancer?","volume":"5","author":"Corthay","year":"2014","journal-title":"Front Immunol"},{"key":"2026062906301063000_14.6.e015150.3","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM198612253152606"},{"key":"2026062906301063000_14.6.e015150.4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20120189"},{"key":"2026062906301063000_14.6.e015150.5","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12528"},{"key":"2026062906301063000_14.6.e015150.6","doi-asserted-by":"crossref","DOI":"10.1097\/MD.0000000000045114","article-title":"Mentzer Index in breast cancer: Insights into anemia and tumor progression \u2013 a narrative review","volume":"104","author":"Obeagu","year":"2025","journal-title":"Medicine (Baltimore)"},{"key":"2026062906301063000_14.6.e015150.7","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1055\/s-0034-1370768","article-title":"Current status of use of erythropoietic agents in cancer patients","volume":"40","author":"Glaspy","year":"2014","journal-title":"Semin Thromb Hemost"},{"key":"2026062906301063000_14.6.e015150.8","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.60.050307.110718"},{"key":"2026062906301063000_14.6.e015150.9","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1038\/s41586-025-09824-z","article-title":"Erythropoietin receptor on cDC1s dictates immune tolerance","volume":"650","author":"Zhang","year":"2026","journal-title":"Nature"},{"key":"2026062906301063000_14.6.e015150.10","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.201512012"},{"key":"2026062906301063000_14.6.e015150.11","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2016.00109","article-title":"A Metabolic Immune Checkpoint: Adenosine in Tumor Microenvironment","volume":"7","author":"Ohta","year":"2016","journal-title":"Front Immunol"},{"key":"2026062906301063000_14.6.e015150.12","doi-asserted-by":"publisher","DOI":"10.1186\/s12943-019-1022-2"},{"key":"2026062906301063000_14.6.e015150.13","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20030590"},{"key":"2026062906301063000_14.6.e015150.14","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M701465200"},{"key":"2026062906301063000_14.6.e015150.15","doi-asserted-by":"crossref","DOI":"10.3389\/fimmu.2018.01324","article-title":"New Insights Into the Regulation of Natural-Killer Group 2 Member D (NKG2D) and NKG2D-Ligands: Endoplasmic Reticulum Stress and CEA-Related Cell Adhesion Molecule 1","volume":"9","author":"Hosomi","year":"2018","journal-title":"Front Immunol"},{"key":"2026062906301063000_14.6.e015150.16","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-19-0761"},{"key":"2026062906301063000_14.6.e015150.17","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1038\/s43018-025-00979-2","article-title":"Tumor antigens preferentially derive from unmutated genomic sequences in melanoma and non-small cell lung cancer","volume":"6","author":"Apavaloaei","year":"2025","journal-title":"Nat Cancer"},{"key":"2026062906301063000_14.6.e015150.18","doi-asserted-by":"crossref","unstructured":"Ely ZA , Kulstad ZJ , Gunaydin G , et al . 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