Irreversible electroporation with intratumoral plant virus immunotherapy induces systemic immunity in a metastatic model of pancreatic cancer.

Pancreatic cancer remains highly resistant to immunotherapy, necessitating innovative strategies. This study explores a novel combination of irreversible electroporation (IRE) and plant virus-based nanoparticles to enhance immune responses in pancreatic ductal adenocarcinoma (PDAC). IRE is a non-thermal tumor ablation technique already in clinical use, but it often fails to prevent metastasis. Plant viral nanoparticles, such as cowpea mosaic virus (CPMV), have shown potent immune-stimulating properties in various cancer models. Using an immunocompetent orthotopic PDAC mouse model with liver metastases, we evaluated the impact of combining IRE and intratumoral CPMV. Combination therapy significantly improved survival and increased infiltration of activated, profilerating CD8⁺ T cells compared to either treatment alone. Notably, liver metastases from treated mice also showed elevated CD8⁺ T and NK cell infiltration. Further, lymph node analysis revealed enhanced dendritic cell maturation and expansion of CD8⁺ effector memory T cells. These results suggest that IRE and CPMV synergize to generate robust local and systemic anti-tumor immunity. This combinatorial strategy effectively converts immunologically "cold" tumors into "hot" tumors, offering a promising approach that can be feasibly translated to PDAC patients.