{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T19:39:31Z","timestamp":1790883571142,"version":"4.1.0"},"reference-count":76,"publisher":"American Society for Clinical Investigation","issue":"10","license":[{"start":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T00:00:00Z","timestamp":1778803200000},"content-version":"vor","delay-in-days":66,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Osaka Cancer Society","award":["No number"],"award-info":[{"award-number":["No number"]}]},{"DOI":"10.13039\/100031495","name":"YOKOYAMA Foundation for Clinical Pharmacology","doi-asserted-by":"crossref","award":["No number"],"award-info":[{"award-number":["No number"]}],"id":[{"id":"10.13039\/100031495","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100019356","name":"SGH Foundation","doi-asserted-by":"crossref","award":["No number"],"award-info":[{"award-number":["No number"]}],"id":[{"id":"10.13039\/100019356","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100008880","name":"Kanae Foundation for the Promotion of Medical Science","doi-asserted-by":"crossref","award":["No number"],"award-info":[{"award-number":["No number"]}],"id":[{"id":"10.13039\/501100008880","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,5,15]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) targeting the programmed cell death 1 axis have revolutionized metastatic non\u2013small cell lung cancer (mNSCLC) treatment. However, disease progression remains a concern, and the role of the complex tumor microenvironment (TME) in treatment failure is not fully understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>In this biomarker study involving 103 patients with mNSCLC, including 81 patients who received ICI treatment, we evaluated the association between heterogeneous immune cell subsets and ICI efficacy through single-cell spatial profiling of pretreatment tumor tissue, using a 29-marker multiplex IHC platform built for in-depth dissection of the TME.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Among various types of intratumoral lymphocytes, including Th1, Treg, and NK cells, only CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells (tumor-infiltrating lymphocytes [TILs]) were associated with ICI efficacy. Computational tissue segmentation underscored the importance of direct physical interactions between CD8\n                      <jats:sup>+<\/jats:sup>\n                      TILs and cancer cells for ICI efficacy. TIL phenotyping identified CD39\/CD103\/Ki-67 positivity as a hallmark of exhausted yet functional tumor-reactive CD8\n                      <jats:sup>+<\/jats:sup>\n                      TILs. Immunosuppressive tumor-associated macrophages (TAMs) and cancer-associated fibroblasts were independent unfavorable adversaries. High CD73 expression on cancer cells was suggested to confer tolerance to ICI in\n                      <jats:italic>EGFR\/ALK<\/jats:italic>\n                      -oncogene\n                      <jats:sup>+<\/jats:sup>\n                      NSCLC, potentially through M2-TAM accumulation and aberrant angiogenesis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>Our study delineates the clinical relevance of heterogeneous immune cell subsets in ICI-treated mNSCLC, aiding the development of targeted therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>Osaka Cancer Society, KANAE Foundation for the Promotion of Medical Science, SGH Foundation, and YOKOYAMA Foundation for Clinical Pharmacology.<\/jats:p>\n                  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