Bioelectrical Regulation of Innate Immunity in Pancreatic Cancer Cells

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal human cancers and remains largely resistant to current immunotherapies. Although the immunosuppressive tumor microenvironment contributes to this resistance, tumor-intrinsic mechanisms that regulate innate immune activation in PDAC are poorly understood. Recent clinical and preclinical studies show that combining DNA-damaging therapies with immunotherapy can improve antitumor responses, highlighting the importance of nucleic acid–sensing innate immune pathways within PDAC cells themselves. Our transcriptomic analyses reveal that PDAC cells upregulate electrophysiology-related genes, including multiple potassium (K..) channels and the calcium-handling protein Junctophilin-2 (JPH2), in response to genotoxic stress. These findings suggest that PDAC cells may repurpose bioelectrical signaling to regulate nucleic acid sensing and suppress innate immune activation. We therefore hypothesize that bioelectrical mechanisms modulate tumor-intrinsic nucleic acid sensing in PDAC to promote cancer cell survival under genotoxic stress. In Aim 1, we will define how JPH2 sequesters cytosolic nucleic acids through condensate formation and regulates innate immune activation in PDAC cells. In Aim 2, we will determine how potassium channel activity and membrane potential influence nucleic acid sensing and PDAC responses to DNA-damaging therapies. Together, these studies will establish a new conceptual framework linking ion channel signaling to tumor-intrinsic innate immunity and identify novel strategies to enhance immunotherapy efficacy in pancreatic cancer. Project Number: 5P20GM109024-09 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Ang Guo | Institution: NORTH DAKOTA STATE UNIVERSITY, FARGO, ND | Award Amount: $78,612 | Activity Code: P20 | Study Section: ZGM1-RCB-W(C2) View on NIH RePORTER: https://reporter.nih.gov/project-details/11518553