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Updated: Jun 5, 2026
Reprogramming Pancreatic Ductal Adenocarcinoma to Pluripotency
Published on: February 2, 2024
Anti-PD-1 blockade reverses low-intensity electric stimulation-driven pancreatic cancer progression
Lingmin Jiang1, Xiyuan Li2, Dejun Zeng3
1Department of Pancreatobiliary Surgery, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
Background:
Irreversible electroporation (IRE) represents a potential therapeutic approach for pancreatic ductal adenocarcinoma (PDAC). However, differences in tumor size and shape can lead to an uneven distribution of the electric field, causing certain cells to receive only low-intensity electric stimulation (LIES). This study aimed to explore the tumor immune microenvironment following LIES and evaluate the synergistic antitumor effects of LIES combined with anti-PD-1 blockade.
Methods:
Orthotopic PDAC models in mice were treated with LIES with or without anti-PD-1 blockade. In vitro assays under varying electric fields assessed tumor cell viability, migration, and epithelial-mesenchymal transition (EMT). Tumor immune microenvironment remodeling was comprehensively profiled using flow cytometry, multicolor immunofluorescence, and single-cell RNA sequencing (scRNA-seq). The underlying mechanism was further investigated via bulk RNA sequencing and validated in vitro.
Results:
Orthotopic PDAC models were established and utilized for the first time to evaluate the immune modulation and macrophage polarization effects of LIES. Cell-based assays were conducted to assess the impact of varying field strengths on cell proliferation and migration. Anti-PD-1 blockade reversed the tumor growth and systemic antitumor responses following the LIES. Flow cytometry, multicolor immunofluorescence, and scRNA-seq revealed that combination therapy amplified CD8+ T cell activation. Further bulk RNA-seq analysis revealed that LIES activated the JAK2-STAT3 pathway, inducing expression of PD-L1 in PDAC cells.
Conclusions:
Anti-PD-1 blockade can reverse LIES-driven tumor progression by upregulating CD8+ T cell expression. The integration of anti-PD-1 blockade with IRE potentially overcomes the limitations of incomplete ablation within the LIES, thereby improving oncological outcomes.
Insights
Low-intensity electric stimulation (LIES) combined with anti-PD-1 blockade enhances immune response in pancreatic cancer. This combination therapy overcomes limitations of incomplete ablation, improving oncological outcomes by boosting CD8+ T cell activation.
Area of Science:
- Oncology
- Immunotherapy
- Biophysics
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is a challenging cancer.
- Irreversible electroporation (IRE) shows therapeutic promise but faces challenges with uneven electric field distribution.
- Low-intensity electric stimulation (LIES) can result from uneven fields, impacting treatment efficacy.
Purpose of the Study:
- To investigate the tumor immune microenvironment following LIES in PDAC.
- To evaluate the synergistic antitumor effects of combining LIES with anti-PD-1 blockade.
- To explore the underlying mechanisms of LIES and combination therapy.
Main Methods:
- Orthotopic PDAC mouse models were treated with LIES +/- anti-PD-1 blockade.
- In vitro assays assessed tumor cell viability, migration, and EMT under varying electric fields.
- Immune microenvironment profiling utilized flow cytometry, immunofluorescence, and scRNA-seq.
- Mechanism exploration involved bulk RNA sequencing.
Main Results:
- LIES modulated the immune microenvironment and macrophage polarization.
- Anti-PD-1 blockade reversed LIES-induced tumor growth and enhanced systemic antitumor responses.
- Combination therapy significantly amplified CD8+ T cell activation.
- LIES activated the JAK2-STAT3 pathway, increasing PD-L1 expression in PDAC cells.
Conclusions:
- Anti-PD-1 blockade counteracts LIES-driven tumor progression by enhancing CD8+ T cell activity.
- Combining anti-PD-1 blockade with IRE (via LIES) may overcome incomplete ablation limitations.
- This integrated approach holds potential for improved oncological outcomes in PDAC.
