Modulating pancreatic juice ENPP1-STING crosstalk to reprogram the tumor immune landscape in pancreatic cancer

Background: Pancreatic cancer is among the deadliest solid tumors, primarily due to its profoundly immunosuppressive tumor microenvironment (TME) characterized by poor T-cell infiltration and resistance to immunotherapy. We previously demonstrated that modulation of the STING (Stimulator of Interferon Genes) pathway in hepatic stellate cells, controlled by the autophagy adaptors NBR1 and p62, can convert hepatocellular carcinoma from a “cold” to a “hot” immune phenotype (Molecular Cell, Nishimura S., 2024). These findings highlight the therapeutic potential of precise STING pathway regulation within the stromal compartment. Objective: This study aims to elucidate how ENPP1 (ecto-nucleotide pyrophosphatase/phosphodiesterase 1), an enzyme highly enriched in pancreatic juice, shapes the pancreatic TME by modulating extracellular cGAMP availability and STING activation. Because ENPP1 degrades cGAMP-the essential second messenger driving STING signaling-we hypothesize that elevated ENPP1 activity suppresses innate immune sensing and promotes a cold TME in pancreatic cancer. Methods: We will analyze pancreatic juice and matched tumor tissues from patients undergoing pancreatic surgery. ENPP1 enzymatic activity, cGAMP degradation capacity, and STING pathway activation (TBK1/IRF3 phosphorylation, type I interferon signatures) will be quantified. Immune profiling will be performed to assess correlations with T-cell infiltration, myeloid composition, and markers of immune exclusion. We will further evaluate whether ENPP1 levels are associated with treatment resistance or clinical outcomes. Results and Significance: We anticipate that high ENPP1 activity will correlate with suppressed STING signaling and reduced immune infiltration, defining a mechanism by which pancreatic tumors maintain an immunologically cold TME. This work has the potential to establish ENPP1 as a biomarker for therapeutic resistance and to support the development of ENPP1-STING-targeted strategies-such as ENPP1 inhibition or cGAMP stabilization-to convert pancreatic tumors into a more immune-responsive state. Pancreatic juice-based immune monitoring may provide a minimally invasive tool for real-time assessment of TME immune status.