Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer

Yu C. J. CheyCentre for Cancer Biology

Bassam KashgariHudson Institute of Medical Research

Louise McLeodHudson Institute of Medical Research

Georgette A. RadfordCentre for Cancer Biology

Linden J. GearingHudson Institute of Medical Research

Ruby DawsonCentre for Cancer Biology

Malvika KharbandaCentre for Cancer Biology

Joanne LundyHudson Institute of Medical Research

Daniel CroaghMonash Health

Charlotte Girard-Guyonvarc’h

Nature Communications·February 7, 2026

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Abstract

Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our discovery that ASC-containing inflammasomes promote PDAC by acting as a molecular bridge between innate immunity, mitochondrial dysfunction and metabolic reprogramming provides the rationale to therapeutically target ASC in cancers.

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