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To address these barriers, we developed a novel combinatorial approach: engineering CAR-T cells with third-generation oncolytic adenoviruses (OAd) to enable targeted viral delivery and sustained immune activation. Unlike conventional OAd administration, this strategy leverages CAR-T cells as tumor-tropic vectors for localized oncolysis and cytokine modulation.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>CD70-specific CAR-T cells were transduced with two third-generation OAds (E1B19K\/E3-deleted, replication-selective): OAd-GFP (control) or OAd-IL15 (TS-2021), generating CAR-T<jats:sup>OAd\u2212GFP<\/jats:sup> and CAR-T<jats:sup>TS\u22122021<\/jats:sup>. Viral replication kinetics and CAR-T expansion were assessed in vitro. OAd delivery efficiency was quantified by co-culturing CAR-T<jats:sup>OAd<\/jats:sup> cells with GBM cells. Flow cytometry was used to analyze IL15-mediated effects on stem-like markers (CCR7, CD45RA) and exhaustion markers (PD-1, TIM-3, and LAG-3) after repeated antigen stimulation. Antitumor activity was evaluated in vitro using cytotoxicity assays and in NCG mice bearing orthotopic GBM xenografts. Mechanistic studies were conducted using RNA-seq and Western blotting.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>In this study, we found that genetically engineered OAd-GFP can specifically replicate within CAR-T cells and be precisely delivered to GBM through an antigen-specific mechanism. Prolonged antigen stimulation induced T-cell exhaustion, limiting the efficacy of CAR-T therapy. TS-2021-infected CAR-T cells exhibited enhanced expansion and persistence in vitro, with reduced expression of exhaustion markers under sustained antigen stimulation. IL15 autocrine signaling activated JAK-STAT and MAPK-ERK pathways. This process repaired the DNA damage induced by OAd in CAR-T cells and maintained their expansion and persistence. By combining OAd-mediated oncolysis with IL15-driven CAR-T persistence, CAR-T<jats:sup>TS\u22122021<\/jats:sup> cells demonstrated potent antitumor efficacy against GBM both in vitro and in vivo.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>By integrating IL15-armed OAd into CAR-T cells, we demonstrate a synergistic strategy that simultaneously enhances viral oncolysis, sustains T-cell persistence, and counteracts GBM immunosuppression. This approach addresses both antigenic heterogeneity and microenvironment-driven resistance, providing a translatable paradigm for solid tumor immunotherapy.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s13046-025-03431-6","type":"journal-article","created":{"date-parts":[[2025,6,5]],"date-time":"2025-06-05T09:32:01Z","timestamp":1749115921000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["CD70 CAR-T cells empowered by TS-2021 through ex vivo transduction show potent antitumor efficacy against glioblastoma"],"prefix":"10.1186","volume":"44","author":[{"given":"Sheng","family":"Fang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiankun","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yida","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peiwen","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiqiang","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiajia","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenxin","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junwen","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fusheng","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"issue":"8","key":"3431_CR1","first-page":"1073","volume":"22","author":"PY Wen","year":"2020","unstructured":"Wen PY, Weller M, Lee EQ, Alexander BM, Barnholtz-Sloan JS, Barthel FP, et al. 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