{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T19:01:04Z","timestamp":1791054064833,"version":"4.1.0"},"reference-count":24,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,9]],"date-time":"2025-07-09T00:00:00Z","timestamp":1752019200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Approximately 20% of patients with non-small cell lung cancer (NSCLC) are diagnosed with brain metastases (BM), which are associated with poor prognosis. Pembrolizumab has shown promising results in advanced NSCLC with PD-L1 \u2265 50%, including patients with BM. Silibinin is a flavonolignan with known blood-brain barrier permeability and anti-BM activity associated with inhibition of the STAT3\/TIMP1 signaling axis. To the best of our knowledge, this is the first clinical evidence of combining silibinin with pembrolizumab to achieve a durable partial response in BM, lasting over 9 months.<\/jats:p><\/jats:sec><jats:sec><jats:title>Case Report<\/jats:title><jats:p>We present the case of a 72-year-old male with stage IVB lung adenocarcinoma and BM, who achieved durable intracranial tumor control with a combination of pembrolizumab and silibinin supplementation. Initial treatment with brain hypofractionated stereotactic radiotherapy and pembrolizumab led to a 14-month partial response. Progression occurred with a new jejunal metastasis and increasing temporal brain lesion. After declining whole-brain radiotherapy, the patient continued pembrolizumab with silibinin (630 mg\/day), on a compassionate basis. At 2 months, a partial response in the temporal lobe lesion was observed, and at 9 months, nearly complete intracranial response was achieved with no extracranial progression. Molecular analysis revealed high PD-L1 expression and a METex14, potentially enhancing the response to immunotherapy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>This case highlights the potential of silibinin as an adjuvant therapy to enhance anti-PD-1 efficacy in brain metastases, possibly by targeting STAT3\/TIMP1-driven immunosuppressive astrocytes. Further investigation of the role of silibinin in improving immunotherapy outcomes in advanced lung cancer patients with BM is required.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2025.1612327","type":"journal-article","created":{"date-parts":[[2025,7,10]],"date-time":"2025-07-10T05:45:24Z","timestamp":1752126324000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["The STAT3\/TIMP1 inhibitor silibinin overcomes secondary immunoresistance to pembrolizumab in brain metastases from METex14 skipping mutated non-small cell lung cancer: a case report"],"prefix":"10.3389","volume":"12","author":[{"given":"Joaquim","family":"Bosch-Barrera","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elia","family":"Sais","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduard","family":"Teixidor-Vil\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen","family":"V\u00e1squez-Dongo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"Hernandez-Mart\u00ednez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alvaro","family":"Romera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mel.lina","family":"Pinsach-Abuin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernat","family":"del Olmo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gl\u00f2ria","family":"Oliveras","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Polonio-Alcal\u00e1","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Verdura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miriam","family":"Soriano-Gamero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Pineda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Rosales","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier A.","family":"Menendez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-024-56046-w","article-title":"Treatment outcomes and prognostic factors in patients with driver mutant non-small cell lung cancer and de novo brain metastases.","volume":"14","author":"Kahraman","year":"2024","journal-title":"Scientific Rep."},{"key":"B2","doi-asserted-by":"publisher","first-page":"100205","DOI":"10.1016\/J.JTOCRR.2021.100205","article-title":"Outcomes With pembrolizumab monotherapy in patients with programmed death-ligand 1-positive NSCLC with brain metastases: Pooled analysis of KEYNOTE-001, 010, 024, and 042.","volume":"2","author":"Mansfield","year":"2021","journal-title":"JTO Clin Res Rep."},{"key":"B3","doi-asserted-by":"publisher","first-page":"102067","DOI":"10.1016\/J.CTRV.2020.102067","article-title":"Immunotherapy in NSCLC patients with brain metastases. 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