{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T05:08:14Z","timestamp":1780549694721,"version":"3.54.1"},"reference-count":38,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T00:00:00Z","timestamp":1779840000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"JSPS Grant-in-Aid for Scientific Research","award":["19K08625"],"award-info":[{"award-number":["19K08625"]}]},{"name":"JSPS Grant-in-Aid for Scientific Research","award":["19H03667"],"award-info":[{"award-number":["19H03667"]}]},{"name":"JSPS Grant-in-Aid for Scientific Research","award":["22H03078"],"award-info":[{"award-number":["22H03078"]}]},{"name":"JSPS Grant-in-Aid for Scientific Research","award":["23K27688"],"award-info":[{"award-number":["23K27688"]}]},{"name":"JSPS Grant-in-Aid for Scientific Research","award":["26K02424"],"award-info":[{"award-number":["26K02424"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>Immune checkpoint inhibitors (ICIs) show limited efficacy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma due to its non-inflamed tumor microenvironment (TME). While quadruple therapy combining chemotherapy, anti-programmed death-ligand 1 (PD-L1), and anti-vascular endothelial growth factor (VEGF) antibodies has shown inconsistent results in EGFR-tyrosine kinase inhibitor (TKI)-pretreated patients, whether anti-VEGF therapy can modulate the intrinsic non-inflamed TME remains unknown. We employed an EGFR-TKI-na\u00efve syngeneic Egfr-mutant mouse model and evaluated effects of anti-VEGF, anti-PD-L1, carboplatin, and paclitaxel as monotherapies and combinations, with TME analysis via immunohistochemistry (IHC), flow cytometry, and RNA sequencing. Anti-PD-L1 showed no antitumor effect, and adding anti-VEGF failed to convert the TME to an inflamed status. Although paclitaxel\u2014but not carboplatin\u2014combined with low-dose anti-VEGF inhibited tumor growth, adding anti-PD-L1 provided no benefit, indicating the anti-VEGF-A antibody evaluated here has a limited role in sensitizing tumors to anti-PD-L1 regardless of chemotherapy. CD8+ T-cell depletion did not attenuate the effect of paclitaxel plus low-dose anti-VEGF, and IHC and RNA sequencing revealed increased natural killer cell infiltration, suggesting a CD8+ T-cell-independent, innate immune mechanism. These findings provide preclinical evidence that the evaluated anti-VEGF has limited immunomodulatory activity in EGFR-TKI-na\u00efve Egfr-mutant tumors with a non-inflamed TME, and suggest immunotherapeutic strategies beyond CD8+ T-cell-mediated immunity warrant investigation.<\/jats:p>","DOI":"10.3390\/curroncol33060315","type":"journal-article","created":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T14:36:56Z","timestamp":1779892616000},"page":"315","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Limited Immune-Mediated Efficacy of Anti-PD-L1\/VEGF in EGFR-TKI-Na\u00efve Egfr-Mutant Lung Cancer with Non-Inflamed Tumor Microenvironment"],"prefix":"10.3390","volume":"33","author":[{"given":"Atsuko","family":"Hirabae","sequence":"first","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadahiro","family":"Kuribayashi","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuta","family":"Tomida","sequence":"additional","affiliation":[{"name":"Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sachi","family":"Okawa","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takamasa","family":"Nakasuka","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1591-1937","authenticated-orcid":false,"given":"Kazuya","family":"Nishii","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2526-0242","authenticated-orcid":false,"given":"Jun","family":"Nishimura","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Go","family":"Makimoto","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5072-3061","authenticated-orcid":false,"given":"Kiichiro","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Center for Comprehensive Genomic Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4946-0123","authenticated-orcid":false,"given":"Hisao","family":"Higo","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5637-0762","authenticated-orcid":false,"given":"Kammei","family":"Rai","sequence":"additional","affiliation":[{"name":"Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2966-106X","authenticated-orcid":false,"given":"Eiki","family":"Ichihara","sequence":"additional","affiliation":[{"name":"Center for Clinical Oncology, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyuki","family":"Hotta","sequence":"additional","affiliation":[{"name":"Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5731-3786","authenticated-orcid":false,"given":"Masamichi","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Product Research Department, Kamakura Research Laboratories, Chugai Pharmaceutical Co., Ltd., Kamakura 247-8530, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yosuke","family":"Togashi","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshinobu","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Hematology, Oncology and Respiratory Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katsuyuki","family":"Kiura","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5180-3933","authenticated-orcid":false,"given":"Kadoaki","family":"Ohashi","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Okayama University Hospital, Okayama 700-8558, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1350","DOI":"10.1126\/science.aar4060","article-title":"Cancer immunotherapy using checkpoint blockade","volume":"359","author":"Ribas","year":"2018","journal-title":"Science"},{"key":"ref_2","first-page":"12","article-title":"Cancer Statistics, 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