Tumor Treating Fields (TTFields) potentiate cisplatin efficacy and remodel the transcriptional landscape in preclinical models of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a 5-year survival rate of 3.2% in metastatic cases. Cisplatin, a DNA-damaging agent, offers minimal benefit due to PDAC's altered DNA repair and protective stroma. Tumor Treating Fields (TTFields), low intensity alternating electric fields that disrupt mitosis, have shown promise in other solid tumors. We investigated whether TTFields enhance cisplatin efficacy in PDAC and explored the underlying biology. PDAC cell lines were treated with TTFields and cisplatin alone or in combination. Assays assessed viability, migration, and clonogenic survival. Orthotopic mouse models evaluated tumor volume. Mechanistic studies included KRAS signaling analysis and RNA sequencing. TTFields significantly reduced PDAC cell viability, migration, and clonogenic survival, with the strongest effects in combination with cisplatin. In vivo, combined therapy achieved ∼85% tumor volume reduction. Molecular profiling revealed suppression of KRAS-driven signaling, stromal activation, and survival pathways beyond single-agent effects. Transcriptomic analysis showed alteration of immunogenic tumor microenvironment, downregulation of inflammatory survival signaling, and upregulation of genes linked to cytoskeletal and mitochondrial remodeling, changes predicted to limit tumor spread and promote apoptosis. TTFields potentiate cisplatin's therapeutic impact in PDAC and reveal a novel biology where electrical and chemical stress converge to reprogram tumor survival. This well tolerated multimodal strategy offers a promising avenue for improving outcomes in PDAC, a cancer urgently needing more effective treatments.