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Adv."],"published-print":{"date-parts":[[2026,9,11]]},"abstract":"<jats:p>\n                    The efficacy of immune checkpoint blockade (ICB) in lung adenocarcinoma (LUAD) is limited by primary or acquired resistance, especially in genetically defined subsets. We investigated the impact of\n                    <jats:italic toggle=\"yes\">KRAS\/TP53<\/jats:italic>\n                    co-mutation on ICB response. Our analysis reveals that\n                    <jats:italic toggle=\"yes\">KRAS\/TP53<\/jats:italic>\n                    co-mutation is associated with favorable ICB outcomes, a phenotype orchestrated by secreted phosphoprotein 1 (SPP1). Mechanistically, mutant p53 and\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    exert opposing effects on SPP1. Mutant p53 synergizes with transcription factor FOXA1 to repress\n                    <jats:italic toggle=\"yes\">SPP1<\/jats:italic>\n                    transcription, whereas\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    activates the mitogen-activated protein kinase (MAPK)\u2013extracellular signal\u2013regulated kinase (ERK)\u2013signal transducer and activator of transcription 1 (STAT1) axis to up-regulate\n                    <jats:italic toggle=\"yes\">SPP1<\/jats:italic>\n                    . Consequently, reduced SPP1 level in\n                    <jats:italic toggle=\"yes\">KRAS\/TP53<\/jats:italic>\n                    co-mutant LUAD impairs myeloid-derived suppressor cell (MDSC) recruitment and increases CD8+ T cell infiltration. Notably, SPP1 blockade synergizes with anti\u2013programmed death-1 (PD-1) therapy to suppress tumor growth in\n                    <jats:italic toggle=\"yes\">KRAS<\/jats:italic>\n                    -mutant xenograft models. Collectively, we delineate a mutant p53\u2013FOXA1\u2013SPP1 regulatory axis that modulates ICB susceptibility and unveil a synergistic combination therapy strategy.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeg9953","type":"journal-article","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T17:58:29Z","timestamp":1789149509000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["Mutant p53 sensitizes KRAS-driven lung adenocarcinoma to immunotherapy by repressing SPP1"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-6887-8316","authenticated-orcid":true,"given":"Xin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China."},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China."},{"name":"Institute of Thoracic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-2969-4194","authenticated-orcid":true,"given":"Qian","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China."},{"name":"Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai 200032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9168-1824","authenticated-orcid":true,"given":"Wenyue","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China."},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China."},{"name":"Institute of Thoracic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, 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China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China."},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China."},{"name":"Institute of Thoracic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6547-3832","authenticated-orcid":true,"given":"Zhihuang","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, China."},{"name":"Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China."},{"name":"Institute of Thoracic Oncology, Fudan University Shanghai Cancer Center, Shanghai 200032, 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