Anti-PD-1 blockade reverses low-intensity electric stimulation-driven pancreatic cancer progression.

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.