{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:47:03Z","timestamp":1782798423772,"version":"3.54.5"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T00:00:00Z","timestamp":1782777600000},"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. Oncol."],"abstract":"<jats:p>Non-small cell lung cancer (NSCLC) harboring EGFR-sensitizing mutations is typically characterized as an immunologically \u201ccold\u201d phenotype, exhibiting limited response to immune checkpoint inhibitors (ICIs). While EGFR tyrosine kinase inhibitors (EGFR-TKIs) represent the standard of care, acquired resistance is inevitable. Herein, we report a case of advanced NSCLC with an EGFR exon 19 deletion (19del). Following progression on multiple lines of TKI therapy and chemotherapy, the patient achieved a progression-free survival (PFS) of 8 months and an overall survival (OS) of 16 months upon receiving a PD-L1 inhibitor-based combination immunotherapy. To elucidate the mechanisms underlying this unexpected clinical benefit, multiplex immunofluorescence (mIF) analysis was performed on serial biopsy specimens obtained pre-immunotherapy (post-osimertinib progression) and post-immunotherapy progression. Results demonstrated that despite low PD-L1 expression in the pre-immunotherapy \u201cresponsive\u201d specimen, the tumor immune microenvironment (TIME) exhibited a highly \u201cinflamed\u201d profile, characterized by high-density infiltration of T cells and B cells, as well as the formation of mature tertiary lymphoid structures (TLS). Notably, these TLS structures were virtually absent in the post-progression specimen. These preliminary, single-case observations raise the hypothesis that mature TLS formation following EGFR-TKI resistance may be associated with an immunotherapy-responsive TIME in EGFR-mutation NSCLC \u2013 A feature not captured by PD-L1 expression alone. Given the inherent limitations of single-case evidence, these findings are strictly exploratory and hypothesis-generating, and merit further prospective validation in adequately powered cohort studies.<\/jats:p>","DOI":"10.3389\/fonc.2026.1846975","type":"journal-article","created":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T05:40:52Z","timestamp":1782798052000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Efficacy and challenges of immunotherapy in advanced EGFR-mutant NSCLC: a case report"],"prefix":"10.3389","volume":"16","author":[{"given":"Yue","family":"Su","sequence":"first","affiliation":[{"name":"Department of Respiratory and Critical Medicine, Tianjin Chest Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weigang","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Medicine, Tianjin Chest Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Medicine, Tianjin Chest Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwen","family":"Qin","sequence":"additional","affiliation":[{"name":"Department of Respiratory and Critical Medicine, Tianjin Chest Hospital","place":["Tianjin, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,30]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J 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