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Peer-reviewedCC BY 4.0Advanced Science

NCLX Inhibition plus Ca2+ Delivery Potentiates Electroporation and Antitumor Immunity in Pancreatic Ductal Adenocarcinoma

  • Chuanbing Zhao1,2
  • Long He3
  • Yu Lu1,2
  • Zanglong Deng1,2
  • Hongzhen Wei1,2
  • Yunpeng Zhang1,2
  • Ming Yang1,2
  • Tao Yin1,2
  1. 1Department of Pancreatic Surgery Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
  2. 2Sino‐German Laboratory of Personalized Medicine for Pancreatic Cancer Union Hospital Tongji Medical College Huazhong University of Science and Technology Wuhan China
  3. 3Department of Hepato‐Biliary‐Pancreatic Surgery Sichuan Clinical Research Center Sichuan Cancer Center Sichuan Cancer Hospital & Institute Affiliated Cancer Hospital of University of Electronic Science and Technology of China Chengdu China
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Abstract

Irreversible electroporation (IRE) is increasingly used for locally advanced pancreatic ductal adenocarcinoma (PDAC), yet electric‐field heterogeneity leaves a low‐field rim where residual cells survive, and recurrence is frequent, compounded by a profoundly immunosuppressive tumor microenvironment. Here, an electroporation‐synchronized adjuvant strategy is developed that integrates intratumoral Ca2+ delivery with nanoparticle‐mediated inhibition of mitochondrial NCLX using CGP37157 (mPEG–PCL@CGP37157). This regimen markedly enhances cytotoxicity in PDAC cell lines and patient‐derived organoids and significantly improves local control and survival in syngeneic subcutaneous and orthotopic PDAC models, without overt systemic toxicity. Reduced therapeutic efficacy in T cell–deficient hosts demonstrates the importance of adaptive immunity. Mechanistically, EP‐resistant PDAC cells upregulate NCLX to buffer mitochondrial Ca2+ stress. Concurrent Ca2+ delivery and pharmacological NCLX inhibition induce sustained mitochondrial Ca2+ overload, triggering immunogenic GSDMD‐dependent pyroptosis. This is accompanied by enhanced dendritic cell activation and CD8+ T‐cell responses, as well as suppression of a tumor–myeloid SPP1–CD44 axis, promoting pro‐inflammatory macrophage polarization. Collectively, targeting NCLX potentiates the immunogenic effects of IRE and provides a translatable strategy for eliminating residual disease in PDAC.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026nclx,
  title = {{NCLX Inhibition plus Ca2+ Delivery Potentiates Electroporation and Antitumor Immunity in Pancreatic Ductal Adenocarcinoma}},
  author = {Chuanbing Zhao and Long He and Yu Lu and Zanglong Deng and Hongzhen Wei and Yunpeng Zhang and Ming Yang and Tao Yin},
  journal = {Advanced Science},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78288},
  url = {https://doi.org/10.1002/advs.78288},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - NCLX Inhibition plus Ca2+ Delivery Potentiates Electroporation and Antitumor Immunity in Pancreatic Ductal Adenocarcinoma
AU  - Chuanbing Zhao
AU  - Long He
AU  - Yu Lu
AU  - Zanglong Deng
AU  - Hongzhen Wei
AU  - Yunpeng Zhang
AU  - Ming Yang
AU  - Tao Yin
PY  - 2026
DA  - 2026/10/25
JO  - Advanced Science
DO  - 10.1002/advs.78288
UR  - https://doi.org/10.1002/advs.78288
AB  - Irreversible electroporation (IRE) is increasingly used for locally advanced pancreatic ductal adenocarcinoma (PDAC), yet electric‐field heterogeneity leaves a low‐field rim where residual cells survive, and recurrence is frequent, compounded by a profoundly immunosuppressive tumor microenvironment. Here, an electroporation‐synchronized adjuvant strategy is developed that integrates intratumoral Ca2+ delivery with nanoparticle‐mediated inhibition of mitochondrial NCLX using CGP37157 (mPEG–PCL@CGP37157). This regimen markedly enhances cytotoxicity in PDAC cell lines and patient‐derived organoids and significantly improves local control and survival in syngeneic subcutaneous and orthotopic PDAC models, without overt systemic toxicity. Reduced therapeutic efficacy in T cell–deficient hosts demonstrates the importance of adaptive immunity. Mechanistically, EP‐resistant PDAC cells upregulate NCLX to buffer mitochondrial Ca2+ stress. Concurrent Ca2+ delivery and pharmacological NCLX inhibition induce sustained mitochondrial Ca2+ overload, triggering immunogenic GSDMD‐dependent pyroptosis. This is accompanied by enhanced dendritic cell activation and CD8+ T‐cell responses, as well as suppression of a tumor–myeloid SPP1–CD44 axis, promoting pro‐inflammatory macrophage polarization. Collectively, targeting NCLX potentiates the immunogenic effects of IRE and provides a translatable strategy for eliminating residual disease in PDAC.
SN  - 2198-3844
ER  -