{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:54:33Z","timestamp":1791266073375,"version":"4.1.0"},"reference-count":37,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T00:00:00Z","timestamp":1791244800000},"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:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Osimertinib and cisplatin are widely used as standard treatments for non-small cell lung cancer (NSCLC); however, their effects on tumor microenvironment remodeling remain poorly understood. This study investigated whether TREM2-positive tumor-associated macrophages (TAMs) promote immune evasion through the CCL5\/CCL22\u2013CCR5\/CCR4\u2013Treg axis under anticancer treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The spatial and quantitative correlations between TREM2\n                      <jats:sup>+<\/jats:sup>\n                      and FOXP3\n                      <jats:sup>+<\/jats:sup>\n                      cells were assessed using NSCLC patient-derived single-cell RNA sequencing (scRNA-seq) datasets, human lung adenocarcinoma tissue microarrays, and cisplatin-treated mouse lung cancer models. Mediators linking TREM2\n                      <jats:sup>+<\/jats:sup>\n                      and FOXP3\n                      <jats:sup>+<\/jats:sup>\n                      cells were identified by cell\u2013cell communication analysis using CellChat and gene expression profiling of THP-1-derived macrophages treated with osimertinib or cisplatin, with validation in bone marrow\u2013derived macrophages.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      scRNA-seq dataset analysis showed significantly enriched TREM2\n                      <jats:sup>+<\/jats:sup>\n                      and FOXP3\n                      <jats:sup>+<\/jats:sup>\n                      cells in lung adenocarcinoma tissues compared with adjacent normal lung, with a significant positive correlation at the aggregated single-cell level (Spearman\u2019s rho = 0.7323, P &amp;lt; 0.001). CCL5 and CCL22 were identified as key mediators linking TREM2\n                      <jats:sup>+<\/jats:sup>\n                      TAMs and FOXP3\n                      <jats:sup>+<\/jats:sup>\n                      Tregs and were markedly induced by treatment but suppressed by TREM2 knockdown or pharmacologic inhibition. TREM2 overexpression further enhanced their induction. Mechanistically, CCL22 induction was broadly dependent on SYK, Src, AKT, NF-\u03baB, or STAT3 signaling pathways, whereas CCL5 upregulation depended on Src, NF-\u03baB, and STAT3, with SYK involvement varying by cell type. In the orthotopic Lewis lung carcinoma (LLC) model, Trem2 inhibition reduced Treg infiltration and mitigated chemotherapy-associated immune evasion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      These findings indicate that TREM2\n                      <jats:sup>+<\/jats:sup>\n                      TAMs drive CCL5\/CCL22-mediated Treg recruitment and support targeting TREM2 to enhance therapeutic efficacy of standard NSCLC treatments.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1914462","type":"journal-article","created":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T05:21:38Z","timestamp":1791264098000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["TREM2+ macrophages mediate anticancer therapy-induced immune evasion in lung adenocarcinoma via the CCL5\/CCL22-Treg axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Chi Young","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Yonsei University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Jin","family":"Cha","sequence":"additional","affiliation":[{"name":"Department of Pathology, Yonsei University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Kyung","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yonsei University College of Medicine","place":["Seoul, Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon Soo","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Yonsei University College of 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