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Adv."],"published-print":{"date-parts":[[2026,10,23]]},"abstract":"<jats:p>\n                    Most small cell lung cancers (SCLCs) exhibit low immunogenicity and intrinsic resistance to immunotherapy, yet the underlying mechanisms remain poorly understood. Here, we identify\n                    <jats:italic toggle=\"yes\">CREBBP<\/jats:italic>\n                    loss, a frequent genetic alteration in SCLC, as a key suppressor of tumor cell-intrinsic immune responses that drives an immune-cold tumor microenvironment in\n                    <jats:italic toggle=\"yes\">Rb1\/Trp53<\/jats:italic>\n                    -driven autochthonous mouse models. Consistently,\n                    <jats:italic toggle=\"yes\">Crebbp<\/jats:italic>\n                    deletion promotes immune escape in syngeneic SCLC models. Mechanistically,\n                    <jats:italic toggle=\"yes\">Crebbp<\/jats:italic>\n                    loss suppresses\n                    <jats:italic toggle=\"yes\">Sting<\/jats:italic>\n                    and major histocompatibility complex class-I expression by reducing histone H3 acetylation. Notably, HDAC inhibition restores histone acetylation, reactivates these silenced genes, and induces tumor cell-intrinsic immune responses. Moreover, pharmacological HDAC inhibition synergizes with immune checkpoint blockade to suppress tumor growth in both\n                    <jats:italic toggle=\"yes\">Crebbp<\/jats:italic>\n                    -mutant and\n                    <jats:italic toggle=\"yes\">Crebbp<\/jats:italic>\n                    -wild-type SCLCs, with a more prominent effect in\n                    <jats:italic toggle=\"yes\">Crebbp<\/jats:italic>\n                    -mutant tumors. Collectively, these findings establish\n                    <jats:italic toggle=\"yes\">CREBBP<\/jats:italic>\n                    loss as a key mechanism of immune evasion and immunotherapy resistance in SCLC, highlighting HDAC inhibition as a promising strategy to enhance immunotherapy efficacy.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aef1693","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T18:01:42Z","timestamp":1792605702000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["CREBBP loss drives immune evasion by epigenetically silencing STING and MHC-I in small cell lung cancer"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9700-749X","authenticated-orcid":true,"given":"Qing","family":"Gao","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kehong","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Deshen","family":"Pan","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9324-0032","authenticated-orcid":true,"given":"Chaoliang","family":"Xu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yufei","family":"Xi","sequence":"additional","affiliation":[{"name":"Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8738-2053","authenticated-orcid":true,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China."},{"name":"Lung Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arnaud","family":"Augert","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yale School of Medicine, Yale University, New Haven, CT, USA."},{"name":"Yale Cancer 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