Extracellular vesicles from obese visceral adipose promote pancreatic cancer development and resistance to immune checkpoint blockade therapy.

Obesity is correlated with multitype of cancer development, and pancreatic ductal adenocarcinoma (PDAC) in obese patients shows dismal prognosis and resistance to immune checkpoint blockade (ICB) therapy. The molecular mechanism is largely unknown. Here we show that obese visceral adipose tissues (VAT) can communicate with distant PDAC by delivering extracellular vesicle (EV) carrying signal molecules. We reveal that PDAC cells can take in VAT-EVs to their lysosomes where EVs-delivered Cathepsin A (Ctsa) stabilize ribonuclease Rnaset2b to produce free pseudouridines from RNA cleavage. Pseudouridines further activate mast cells via mediating an increase in reactive oxygen species (ROS) generation, which leads to a decrease in the distribution of H3K27me3 at the gene promoter, ultimately inhibiting CD8+ T cell activity, forming an immunosuppressive tumor microenvironment which enhances cancer progression and ICB resistance. We also demonstrate harmful effects of VAT-EV CTSA-pseudouridine-mast cell axis for obesity-related PDAC. Animal experiments indicate that Ctsa knockdown effectively enhances ICB efficacy on PDAC. Our study uncovers a mechanism connecting obesity and cancer which holds promise for developing new therapeutic strategy for obesity-related cancers.