{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T07:35:00Z","timestamp":1771918500042,"version":"3.50.1"},"reference-count":30,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T00:00:00Z","timestamp":1751587200000},"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. Immunol."],"abstract":"<jats:p>Brain metastases occur in 40% of advanced NSCLC patients, with poorer prognosis in squamous subtypes. Immune checkpoint inhibitors (ICIs) combined with chemotherapy have revolutionized treatment, yet data on the systematic treatment of stage IV squamous non-small cell lung cancer with surgery remain limited. A 59-year-old male smoker presented with stage cT4N2M1b IVA squamous NSCLC and a solitary brain metastasis. Next-generation sequencing revealed programmed cell death ligand 1 (PD-L1) high expression (TPS=75%) and TMB-High (28.49 Mut\/Mb) without driver mutations. After pembrolizumab plus platinum-based chemotherapy induced conversion therapy for 3 cycles, the brain lesion achieved pathological complete response (pCR) following resection, while the primary lung tumor showed major pathological response (MPR) post-surgery. Postoperative adjuvant chemoimmunotherapy and 2-year pembrolizumab maintenance were administered. Serial circulating tumor DNA (ctDNA) monitoring remained negative, with no recurrence observed over 50 months. This is the first reported case of long-term survival (PFS &amp;gt;50 months) in a PD-L1-high\/TMB-High squamous NSCLC patient with brain metastasis treated with immunotherapy-based multimodal therapy. Our findings suggest that biomarker-guided strategies integrating systemic therapy, surgery, and MRD monitoring may enable curative potential in select advanced NSCLC patients. Further studies are warranted to validate this \u201csandwich\u201d approach (drug-surgery-drug) and optimize treatment duration.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1601125","type":"journal-article","created":{"date-parts":[[2025,7,4]],"date-time":"2025-07-04T01:20:38Z","timestamp":1751592038000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A stage IV lung squamous cell cancer patient with brain metastases, high PD-L1 &amp; TMB, achieves pCR and long-term survival after immune-chemotherapy and radical surgery: a case report and literature review"],"prefix":"10.3389","volume":"16","author":[{"given":"Xiangyu","family":"Xu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zheng","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/nou099","article-title":"and Davis, FG Incidence of brain metastasis at initial presentation of lung cancer","volume":"17","author":"Villano","year":"2015","journal-title":"Neuro-Oncol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"3780","DOI":"10.3390\/cancers16223780","article-title":"Advances in the management of lung cancer brain metastases","volume":"16","author":"Hockemeyer","year":"2024","journal-title":"Cancers"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1200\/JCO.22.01990","article-title":"Pembrolizumab plus chemotherapy in squamous non-small-cell lung cancer: 5-year update of the phase III KEYNOTE-407 study","volume":"41","author":"Novello","year":"2023","journal-title":"J Clin Oncol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1093\/neuonc\/noad147.093","article-title":"Prognostic factors in non-small cell lung cancer metastatic to the brain","volume":"25","author":"Shelley","year":"2023","journal-title":"Neuro-Oncology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2010.30.1655","article-title":"Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952\u201326001 study","volume":"29","author":"Kocher","year":"2011","journal-title":"J Clin Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2016.3834","article-title":"Estimating survival in patients with lung cancer and brain metastases: an update of the graded prognostic assessment for lung cancer using molecular markers (Lung-molgpa)","volume":"3","author":"Sperduto","year":"2017","journal-title":"JAMA Oncol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"60","DOI":"10.1016\/j.ijrobp.2022.03.020","article-title":"Graded prognostic assessment (gpa) for patients with lung cancer and brain metastases: initial report of the small cell lung cancer gpa and update of the non-small cell lung cancer gpa including the effect of programmed death ligand 1 and other prognostic factors","volume":"114","author":"Sperduto","year":"2022","journal-title":"Int J Radiat Oncol Biol Phys"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctrv.2024.102807","article-title":"Central nervous system metastases in advanced non-small cell lung cancer: A review of the therapeutic landscape","volume":"130","author":"Weller","year":"2024","journal-title":"Cancer Treat Rev"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13237371","article-title":"Lung cancer with brain metastasis\u2014treatment strategies and molecular characteristics","volume":"13","author":"Wang","year":"2024","journal-title":"J Clin Med"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3760\/cma.j.cn112151-20210429-00335","article-title":"Expert consensus on the pathological evaluation of neoadjuvant therapy efficacy for non-small cell lung cancer","volume":"50","year":"2021","journal-title":"Chin J Pathologi"},{"key":"B11","volume-title":"NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines\u00ae): Non-Small Cell Lung Cancer. Version 3.2025","year":""},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3779\/j.issn.1009-3419.2018.08.06","article-title":"Research progress of immunotherapy for brain metastases in patients with drive gene negative NSCLC","volume":"21","author":"Zhang","year":"2018","journal-title":"Zhongguo Fei Ai Za Zhi"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.06.020","article-title":"Outcomes with pembrolizumab plus platinum-based chemotherapy for patients with nsclc and stable brain metastases: pooled analysis of KEYNOTE-021, -189, and -407","volume":"16","author":"Powell","year":"2021","journal-title":"J Thorac Onco"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2023.04.021","article-title":"Systemic and intracranial outcomes with first-line nivolumab plus ipilimumab in patients with metastatic nsclc and baseline brain metastases from checkmate 227 part 1","volume":"18","author":"Reck","year":"2023","journal-title":"J Thorac Oncol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1158\/2326-6066.CIR-15-0064","article-title":"The interplay of immunotherapy and chemotherapy: harnessing potential synergies","volume":"3","author":"Emens","year":"2015","journal-title":"Cancer Immunol Res"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab012","article-title":"Emerging principles of brain immunology and immune checkpoint blockade in brain metastases","volume":"144","author":"Fares","year":"2021","journal-title":"Brain"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000002720","article-title":"Intracranial activity of first-line immune checkpoint inhibitors combined with chemotherapy in advanced non-small cell lung cancer","volume":"136","author":"Huang","year":"2023","journal-title":"Chin Med J"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)32409-7","article-title":"Pembrolizumab versus chemotherapy for previously untreated, PD-L1-expressing, locally advanced or metastatic non-small-cell lung cancer (KEYNOTE-042): a randomized, open-label, controlled, phase 3 trial","volume":"393","author":"Mok","year":"2019","journal-title":"Lancet (London England)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2023.01.011","article-title":"Associations of tissue tumor mutational burden and mutational status with clinical outcomes in KEYNOTE-042: pembrolizumab versus chemotherapy for advanced PD-L1-positive NSCLC","volume":"34","author":"Mok","year":"2023","journal-title":"Ann Oncol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801946","article-title":"Nivolumab plus Ipilimumab in lung cancer with a high tumor mutational burden","volume":"378","author":"Hellmann","year":"2018","journal-title":"N Engl J Med"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/adfm.202312595","article-title":"A multistage-responsive antibody-delivery strategy to improve immunotherapy for NSCLC brain metastasis by ultrasensitive releasing and tumor-anchoring","volume":"34","author":"Li","year":"2024","journal-title":"Adv Funct Mater"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1097\/CM9.0000000000002127","article-title":"Tumor microenvironment in lung cancer-derived brain metastasis","volume":"135","author":"Liu","year":"2022","journal-title":"Chin Med J"},{"key":"B23","doi-asserted-by":"publisher","first-page":"2059874","DOI":"10.1080\/2162402X.2022.2059874","article-title":"Immune suppressive microenvironment in brain metastatic non-small cell lung cancer: comprehensive immune microenvironment profiling of brain metastases versus paired primary lung tumors (GASTO 1060)","volume":"11","author":"Li","year":"2022","journal-title":"Oncoimmunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1007\/s11060-024-04590-w","article-title":"Predictive role of intracranial PD-L1 expression in a real-world cohort of NSCLC patients treated with immune checkpoint inhibition following brain metastasis resection","volume":"167","author":"Wasilewski","year":"2024","journal-title":"J Neuro-Oncol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/JS9.0000000000001921","article-title":"Salvage surgery and conversion surgery for patients with nonsmall cell lung cancer: a narrative review","volume":"111","author":"Yan","year":"2025","journal-title":"Int J Surg"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2023\/4119541","article-title":"Operative versus nonoperative treatment in patients with advanced non-small-cell lung cancer: recommended for surgery","volume":"2023","author":"Wang","year":"2023","journal-title":"Canad Respir J"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.693704","article-title":"Case Report: pathological complete response in a brain-metastatic lung squamous cell carcinoma patient with long-term benefit from chemo-immunotherapy","volume":"11","author":"Hu","year":"2021","journal-title":"Front Oncol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2021.763790","article-title":"Circulating tumor dna and minimal residual disease (mrd) in solid tumors: current horizons and future perspectives","volume":"11","author":"Peng","year":"2021","journal-title":"Front Oncol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02660-6","article-title":"Association between pathologic response and survival after neoadjuvant therapy in lung cancer","volume":"30","author":"Deutsch","year":"2023","journal-title":"Nat Med"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1486","article-title":"Longitudinal undetectable molecular residual disease defines potentially cured population in localized non\u2013small cell lung cancer","volume":"12","author":"Zhang","year":"2022","journal-title":"Cancer Discov"}],"updated-by":[{"DOI":"10.3389\/fimmu.2025.1660020","type":"corrigendum","label":"Corrigendum","source":"publisher","updated":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T00:00:00Z","timestamp":1753142400000}}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1601125\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,22]],"date-time":"2025-07-22T08:00:04Z","timestamp":1753171204000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1601125\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,4]]},"references-count":30,"alternative-id":["10.3389\/fimmu.2025.1601125"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1601125","relation":{"corrigendum":[{"id-type":"doi","id":"10.3389\/fimmu.2025.1660020","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,4]]},"article-number":"1601125"}}