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SenExo-cCCT2 Reprograms Senescence Response and Anti-Tumor Immunity Following FOLFIRINOX Chemotherapy in Pancreatic

Shuncang Zhu1,2, Yinhao Chen1,2, Hongyi Lin1,2

  • 1Shengli Clinical Medical College of Fujian Medical University, Fuzhou, 350001, P. R. China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|July 21, 2025
PubMed

Insights

Chemotherapy combined with immunotherapy shows promise for pancreatic cancer. FOLFIRINOX treatment induces senescent tumor cells via cCCT2, enhancing immune response and improving therapeutic outcomes.

Area of Science:

  • Oncology
  • Cancer Biology
  • Immunotherapy

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) has shown limited therapeutic breakthroughs with current chemotherapy and immunotherapy combinations.
  • Chemotherapy-induced senescence presents a potential strategy to overcome treatment resistance in PDAC.

Purpose of the Study:

  • To investigate the role of chemotherapy-induced senescence in PDAC treatment.
  • To identify molecular mechanisms driving senescence and immune microenvironment modulation.
  • To develop a novel therapeutic strategy combining chemotherapy, senescence induction, and immunotherapy.

Main Methods:

  • Integration of clinical samples with single-cell transcriptomic sequencing, proteomics, and RNA sequencing.
  • Analysis of FOLFIRINOX treatment effects on tumor cell senescence and the tumor immune microenvironment.
  • Development and evaluation of an engineered exosome-loaded circRNA system (SenExo-cCCT2) for targeted delivery.

Main Results:

  • FOLFIRINOX treatment significantly increases the proportion of senescent tumor cells (senTCs) in PDAC, primarily driven by cCCT2.
  • cCCT2 inhibits DNA damage repair, promoting senescence and altering the tumor immune microenvironment by increasing CXCL10 secretion from senTCs.
  • SenExo-cCCT2 enhances FOLFIRINOX-induced senescence, and subsequent anti-PD-L1 therapy promotes immune-mediated clearance of senTCs.

Conclusions:

  • cCCT2 is a key mediator of FOLFIRINOX-induced senescence and immune modulation in PDAC.
  • The combination of FOLFIRINOX, SenExo-cCCT2, and anti-PD-L1 therapy represents a promising strategy to enhance pancreatic cancer treatment efficacy.
Keywords:
CD8+ T‐cellschemotherapycircRNApancreatic ductal adenocarcinomasenescence

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