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author：

Wu, M. (Wu, M..) [1] | Zhang, C. (Zhang, C..) [2] | Zhong, A. (Zhong, A..) [3] | Li, H. (Li, H..) [4] | Zhou, Y. (Zhou, Y..) [5] | Zheng, X. (Zheng, X..) [6] | Zheng, Y. (Zheng, Y..) [7] | Zhang, Y. (Zhang, Y..) [8] | Cao, Y. (Cao, Y..) [9] | Li, Z. (Li, Z..) [10] | Wu, X. (Wu, X..) [12] | Cen, D. (Cen, D..) [13] | Liu, X. (Liu, X..) [14]

Indexed by：

Scopus

Abstract：

Treatment　with　combined　immune　checkpoint　blockade　(CICB)　has　been　considered　as　an　effective　approach　to　increase　the　objective　response　rate　for　cancer　immunotherapy,　but　at　the　cost　of　significantly　increased　immune-related　adverse　events　(irAEs)　and　also　sufferings　from　drug　resistance　due　to　the　transitory　working　manner　of　antibody-based　ICB　inhibitors.　We　introduce　an　antibody-independent　CICB　strategy　using　an　adenoviral　vector　(sgCas9-Adv@TCM)　that　delivers　a　PD-L1　targeted　CRISPR/Cas9　system,　with　a　cell　membrane　cloak　presenting　TIGIT　proteins.　The　vector　could　effectively　accumulate　in　tumors,　allowing　permanent　PD-L1　genome　editing　and　TIGIT/CD155　blocking　through　systemic　administration　while　evading　detection　and　degradation　by　the　immune　system.　The　sgCas9-Adv@TCM　vector　achieved　complete　tumor　regression　in　80%　of　mice　in　a　subcutaneous　hepatocellular　carcinoma　(HCC)　model　by　globally　reshaping　the　tumor　immune　microenvironment　to　elicit　robust　anti-tumor　immunity.　Furthermore,　sgCas9-Adv@TCM　was　proven　to　be　still　competent　and　even　superior　to　the　standard　FDA-approved　CICB　regimen　of　the　combined　anti-PD-L1　and　anti-TIGIT　in　suppressing　tumor　progression,　prolonging　survival,　and　inducing　immunological　memory　of　mice　in　the　orthotopic　HCC　model,　but　with　a　much　lower　risk　of　irAEs.　In　addition,　the　clinical　translation　potential　of　sgCas9-Adv@TCM　was　further　validated　in　the　patient-derived　organoid　(PDO)　and　patient-derived　xenograft　(PDX)　models　from　patients　diagnosed　with　HCC.　Thus,　this　study　presents　a　safe　and　highly　efficient　“stealth”　adenoviral　vector　with　improved　CICB　features　for　cancer　treatment.　©　2025

Keyword：

Adenoviral vector Cancer immunotherapy Genetically engineered cell membrane PD-L1 genome editing TIGIT/CD155 blockade

Community：

  • [ 1 ] [Wu M.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 2 ] [Wu M.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 3 ] [Wu M.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 4 ] [Zhang C.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 5 ] [Zhang C.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 6 ] [Zhang C.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 7 ] [Zhong A.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 8 ] [Zhong A.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 9 ] [Zhong A.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 10 ] [Li H.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 11 ] [Li H.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 12 ] [Li H.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 13 ] [Zhou Y.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 14 ] [Zhou Y.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 15 ] [Zhou Y.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 16 ] [Zheng X.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 17 ] [Zheng X.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 18 ] [Zheng X.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 19 ] [Zheng Y.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 20 ] [Zheng Y.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 21 ] [Zheng Y.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 22 ] [Zhang Y.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 23 ] [Zhang Y.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 24 ] [Zhang Y.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 25 ] [Cao Y.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 26 ] [Cao Y.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 27 ] [Cao Y.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 28 ] [Li Z.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 29 ] [Li Z.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 30 ] [Li Z.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 31 ] [Zhang C.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 32 ] [Zhang C.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 33 ] [Zhang C.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China
  • [ 34 ] [Wu X.]Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Fuzhou, 350025, China
  • [ 35 ] [Cen D.]Department of General Surgery, Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310016, China
  • [ 36 ] [Liu X.]The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou, 350025, China
  • [ 37 ] [Liu X.]The Liver Center of Fujian Province, Fujian Medical University, Fuzhou, 350025, China
  • [ 38 ] [Liu X.]Mengchao Med-X Center, Fuzhou University, Fuzhou, 350116, China

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Fundamental Research

ISSN： 2096-9457

Year： 2025

5 . 7 0 0

JCR@2023

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