{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T07:23:25Z","timestamp":1787729005735,"version":"build-2784847793"},"reference-count":41,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2026,8,10]],"date-time":"2026-08-10T00:00:00Z","timestamp":1786320000000},"content-version":"vor","delay-in-days":9,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82070101"],"award-info":[{"award-number":["82070101"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clinical &amp;amp; Translational Med"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>Anti\u2010PD\u20101 therapy resistance remains a critical barrier in non\u2010small cell lung cancer (NSCLC) management, and the underlying mechanisms are incompletely defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We generated CD155\u2011knockout (KO) NSCLC cell lines using the CRISPR\u2011Cas9 system and performed systematic multi\u2011omics analyses, including single\u2011cell RNA\u2011seq, bulk RNA\u2011seq, proteomics, and metabolomics. The key molecular mechanisms were further validated by immunohistochemistry (IHC), western blotting, and chromatin immunoprecipitation (ChIP). Functional assays assessed cell proliferation, migration, and metabolic phenotypes, while the therapeutic efficacy was assessed in vivo using AAV9_shCD155.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Single\u2010cell sequencing revealed aberrantly high CD155 expression in NSCLC patients with poor response to anti\u2010PD\u20101 therapy. High CD155 expression in NSCLC tissues correlated with unfavourable prognosis. ETS1 was identified as a direct transcriptional driver of CD155. Multi\u2010omics analysis and functional assays demonstrated that CD155 upregulates the expression of key glycolytic proteins (GLUT1, GLUT3, LDHB) by activating the PI3K\/AKT\/HIF\u20101\u03b1 signalling axis, thereby driving glycolytic metabolism, proliferation, and migration of tumour cells. CD155 knockout significantly suppressed these malignant phenotypes. In xenograft mouse models, monotherapy with AAV9_shCD155 effectively inhibited tumour growth and postoperative recurrence. More importantly, in humanised mouse models, combining AAV9_shCD155 with pembrolizumab produced synergistic anti\u2010tumour effects, more significantly suppressing tumour growth and promoting immune cell infiltration into the tumour microenvironment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CD155 mediates anti\u2010PD\u20101 resistance by activating PI3K\/AKT\/HIF\u20101\u03b1\u2010driven glycolytic reprogramming. Targeting CD155 combined with anti\u2010PD\u20101 overcomes resistance, supporting a dual\u2010target therapeutic strategy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key points<\/jats:title>\n                    <jats:p>\n                      <jats:list list-type=\"bullet\">\n                        <jats:list-item>\n                          <jats:p>CD155 is identified as a key driver of anti\u2010PD\u20101 resistance in NSCLC.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>CD155 promotes tumour glycolysis and malignant progression via the PI3K\/AKT\/HIF\u20101\u03b1 signalling axis.<\/jats:p>\n                        <\/jats:list-item>\n                        <jats:list-item>\n                          <jats:p>AAV9_shCD155 combined with anti\u2010PD\u20101 markedly inhibits tumour growth and promotes immune infiltration.<\/jats:p>\n                        <\/jats:list-item>\n                      <\/jats:list>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/ctm2.70741","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T04:59:48Z","timestamp":1786424388000},"source":"Crossref","is-referenced-by-count":0,"title":["Endogenous CD155 drives metabolic reprogramming via PI3K\/AKT\/HIF\u20101\u03b1\u2010glycolysis axis to mediate anti\u2010PD\u20101 resistance in non\u2010small cell lung cancer"],"prefix":"10.1002","volume":"16","author":[{"given":"Wei\u2010Guang","family":"Du","sequence":"first","affiliation":[{"name":"Department of Thoracic Surgery Tangdu Hospital Fourth Military Medical University  Xi'an Shaanxi China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8499-0536","authenticated-orcid":false,"given":"Xi\u2010Yang","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of 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