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author：

Zhu, S. (Zhu, S..) [1] | Chen, Y. (Chen, Y..) [2] | Lin, H. (Lin, H..) [3] | Lu, J. (Lu, J..) [4] | Pan, Y. (Pan, Y..) [5] | Li, G. (Li, G..) [6] | Wu, Y. (Wu, Y..) [7] | Zhang, H. (Zhang, H..) [8] | Huang, X. (Huang, X..) [9] | Chen, H. (Chen, H..) [11] | Jin, L. (Jin, L..) [12] | Huang, M. (Huang, M..) [13] | Liao, C. (Liao, C..) [14] | Huang, L. (Huang, L..) [15] | Tian, Y. (Tian, Y..) [16] | Wang, Z. (Wang, Z..) [17] | Li, Q. (Li, Q..) [18] | Chen, S. (Chen, S..) [19]

Indexed by：

Scopus

Abstract：

Combination　chemotherapy　and　immunotherapy　have　failed　to　achieve　breakthroughs　in　pancreatic　ductal　adenocarcinoma　(PDAC).　Chemotherapy-induced　senescence　is　a　potential　solution　for　this　problem.　This　study　integrates　clinical　samples　with　single-cell　transcriptomic　sequencing,　proteomics,　and　RNA　sequencing　and　reveals　that　FOLFIRINOX　(a　combination　regimen　of　5-fluorouracil,　oxaliplatin,　irinotecan,　and　leucovorin)　treatment　induces　a　higher　proportion　of　senescent　tumor　cells　(senTCs).　This　phenomenon　is　principally　attributed　to　the　presence　of　cCCT2,　which　inhibits　SLX4　condensate-mediated　DNA　damage　repair　pathways　by　regulating　small　ubiquitin-like　modifier　conjugation,　thereby　promoting　tumor　cell　senescence.　In　the　tumor　immune　microenvironment,　cCCT2-overexpressing　senTCs　exhibit　a　senescence-associated　secretory　phenotype　(SASP)　with　preferential　secretion　of　CXCL10,　which　induces　chemotaxis　of　CD8+　T-cells.　Based　on　the　pro-senescence　and　immune-microenvironment-remodeling　effects　of　cCCT2,　an　engineered　exosome-loaded　circRNA　system,　SenExo-cCCT2　is　developed.　When　combined　with　SenExo-cCCT2,　the　FOLFIRINOX　regimen　enhances　the　capacity　of　pancreatic　cancer　cells　to　induce　senescence.　Subsequently,　anti-PD-L1　therapy　facilitates　the　immune-mediated　clearance　of　senTCs,　markedly　improving　the　therapeutic　efficacy　of　combined　chemotherapy　and　immunotherapy　for　pancreatic　cancer.　©　2025　The　Author(s).　Advanced　Science　published　by　Wiley-VCH　GmbH.

Keyword：

CD8+ T-cells chemotherapy circRNA pancreatic ductal adenocarcinoma senescence

Community：

  • [ 1 ] [Zhu S.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 2 ] [Zhu S.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 3 ] [Zhu S.]Fuzhou University, Fuzhou, 350001, China
  • [ 4 ] [Chen Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 5 ] [Chen Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 6 ] [Chen Y.]Fuzhou University, Fuzhou, 350001, China
  • [ 7 ] [Lin H.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 8 ] [Lin H.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 9 ] [Lin H.]Fuzhou University, Fuzhou, 350001, China
  • [ 10 ] [Lu J.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 11 ] [Lu J.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 12 ] [Lu J.]Fuzhou University, Fuzhou, 350001, China
  • [ 13 ] [Pan Y.]Department of General Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
  • [ 14 ] [Li G.]Department of Hepatobiliary Surgery, Fujian Institute of Hepatobiliary Surgery, Fujian Medical University Union Hospital, Fuzhou, 350001, China
  • [ 15 ] [Wu Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 16 ] [Wu Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 17 ] [Wu Y.]Fuzhou University, Fuzhou, 350001, China
  • [ 18 ] [Zhang H.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 19 ] [Zhang H.]Fuzhou University, Fuzhou, 350001, China
  • [ 20 ] [Huang X.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 21 ] [Huang X.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 22 ] [Huang X.]Fuzhou University, Fuzhou, 350001, China
  • [ 23 ] [Chen Y.]College of Biological Science and Engineering, Fuzhou University, Fuzhou, 350108, China
  • [ 24 ] [Chen Y.]Institute of Applied Genomics, Fuzhou University, Fuzhou, 350108, China
  • [ 25 ] [Chen H.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 26 ] [Jin L.]Department of Pathology, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou, 350001, China
  • [ 27 ] [Huang M.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 28 ] [Liao C.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 29 ] [Liao C.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 30 ] [Liao C.]Fuzhou University, Fuzhou, 350001, China
  • [ 31 ] [Huang L.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 32 ] [Huang L.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 33 ] [Huang L.]Fuzhou University, Fuzhou, 350001, China
  • [ 34 ] [Tian Y.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 35 ] [Tian Y.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 36 ] [Tian Y.]Fuzhou University, Fuzhou, 350001, China
  • [ 37 ] [Wang Z.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 38 ] [Wang Z.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 39 ] [Wang Z.]Fuzhou University, Fuzhou, 350001, China
  • [ 40 ] [Li Q.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 41 ] [Li Q.]Fuzhou University, Fuzhou, 350001, China
  • [ 42 ] [Li Q.]Fujian Provincial Institute of Clinical Geriatrics, Fuzhou, 350001, China
  • [ 43 ] [Li Q.]Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China
  • [ 44 ] [Li Q.]Fujian Provincial Center for Geriatrics, Fuzhou, 350001, China
  • [ 45 ] [Chen S.]Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, China
  • [ 46 ] [Chen S.]Department of Hepatobiliary Pancreatic Surgery, Fuzhou University Affiliated Provincial Hospital, Fujian Provincial Hospital, Fuzhou University, Fuzhou, 350001, China
  • [ 47 ] [Chen S.]Fuzhou University, Fuzhou, 350001, China
  • [ 48 ] [Chen S.]Fujian Key Laboratory of Geriatrics, Fuzhou, 350001, China

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Advanced Science

ISSN： 2198-3844

Year： 2025

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JCR@2023

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