{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T18:38:19Z","timestamp":1793039899300,"version":"4.5.0"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T00:00:00Z","timestamp":1771977600000},"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>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs) are a frontline treatment for advanced non-small cell lung cancer (NSCLC), yet 80% of the patients exhibit resistance, creating an urgent need for novel therapeutic strategies. In this study, we investigated the synergistic efficacy of a triple-combination therapy comprising a PD-1 antibody, adoptive NK (natural killer) cells, and an oncolytic adenovirus Ad-anti-TGF-\u03b2RII (encoding a TGF-\u03b2 inhibitor) in NSCLC xenograft mouse models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We investigated the combined effect of Ad-anti-TGF-\u03b2RII and NK cells on PD-1 antibody monotherapy using both\n                      <jats:italic>in vitro<\/jats:italic>\n                      cell experiments and the mouse model of NSCLC. Cytotoxicity assays, quantitative real-time PCR, and western blot analysis demonstrated that Ad-anti-TGF-\u03b2RII exhibited stronger tumor-killing activity compared to the control oncolytic adenovirus Ad-null. Furthermore, cytotoxicity assays and flow cytometry were employed to explore how the combination of Ad-anti-TGF-\u03b2RII and NK cells with PD-1 antibody promotes NK cell proliferation and activation, as well as the potent tumor-killing effect of the combination therapy. In the mouse model of NSCLC, the anti-tumor efficacy of the combination therapy was evaluated by monitoring tumor volume changes, hematoxylin and eosin (H&amp;amp;E) staining. The underlying mechanisms were further investigated using immunofluorescence, immunohistochemistry, quantitative real-time PCR, western blot, and flow cytometry.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The triple-combination therapy markedly inhibited tumor growth, augmented NK cell cytotoxicity and elevated the expression levels of perforin, granzyme B, and IFN-\u03b3. Furthermore, it significantly increased lymphocyte recruitment and infiltration into tumor tissue. Comprehensive analysis demonstrated the favorable safety profile of this therapeutic regimen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our findings suggest that the combination of a PD-1 antibody, NK cells, and the oncolytic adenovirus Ad-anti-TGF-\u03b2RII represents a promising therapeutic strategy for NSCLC by remodeling the tumor microenvironment (TME) to overcome ICI resistance.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1759236","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T07:06:11Z","timestamp":1772003171000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Oncolytic adenovirus encoding a TGF-\u03b2 inhibitor synergizes with PD-1 blockade to potentiate NK cell cytotoxicity against 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