{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:16:46Z","timestamp":1791407806149,"version":"4.3.3"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T00:00:00Z","timestamp":1781481600000},"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>The efficacy of oncolytic adenoviruses in colorectal cancer models is constrained by a treatment-induced limitation: the high-dose, repetitive administration required for sustained oncolysis promotes chronic antigen exposure and tumor microenvironmental stress, driving CD8+ T cells into a state of exhaustion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>To mitigate this, we constructed an oncolytic adenovirus, ADV-PTD4-D3, engineered for intratumoral expression of a peptide inhibitor of CDK4\/6. This local strategy aims to retain immunomodulatory potential while minimizing systemic exposure. In syngeneic murine models, ADV-PTD4-D3 demonstrated improved tumor control and the ability to induce robust, antigen-specific immunological memory, with its therapeutic effect being primarily dependent on CD8+ T cells. Notably, it also exhibited potent antitumor activity in a humanized xenograft model and showed no evidence of significant off-target toxicity in immunocompetent hosts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The mechanism involves a signaling axis where viral-mediated CDK4\/6 inhibition reduces retinoblastoma (Rb) protein phosphorylation. This decrease relieves Rb-mediated sequestration of the NF-kB p65 subunit, allowing p65 nuclear translocation and transcriptional upregulation of the T-cell chemoattractant CCL5, a factor linked to favorable patient prognosis. Thus, ADV-PTD4-D3 promotes a T-cell-inflamed microenvironment by providing a sustained chemotactic signal CCL5 for CD8+ T cell recruitment. Furthermore, this treatment strategy successfully reverses the functional exhaustion of infiltrating CD8+ T cells, thereby addressing two major barriers to effective therapy: inadequate infiltration and functional exhaustion. By modifying the tumor microenvironment in this way, the armed virus addresses two factors that limit T-cell-based immunotherapies: inadequate infiltration and functional exhaustion. Correspondingly, ADV-PTD4-D3 treatment improved the antitumor response to both PD-1 blockade and CAR-T cell therapy in combination studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>These findings suggest that engineering oncolytic viruses to locally modulate pathways involved in T cell exhaustion represents a viable and translatable strategy for enhancing antitumor immunity.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1839684","type":"journal-article","created":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T05:37:45Z","timestamp":1781501865000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["A CDK4\/6 inhibitor-armed oncolytic adenovirus reverses T cell exhaustion through the Rb-p65-CCL5 pathway and potentiates the antitumor activity of anti-PD-1 or CAR-T therapy in colorectal cancer"],"prefix":"10.3389","volume":"17","author":[{"given":"Dan","family":"Zhou","sequence":"first","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School, Medical School, Nanjing University","place":["Nanjing, China"]},{"name":"Jinan Microecological Biomedicine Shandong Laboratory, Building 1, Jinan Medical and Health Science and Technology Innovation Industrial Park","place":["Jinan, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beibei","family":"Ran","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Pharmaceutical Biotechnology, Division of Hepatobiliary and Transplantation Surgery, Department of General Surgery Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical 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