Extracellular vesicles from obese visceral adipose promote pancreatic cancer development and resistance to immune checkpoint blockade therapy [ATAC-seq]

Obesity is correlated with multitype of cancer development, and pancreatic ductal adenocarcinoma (PDAC) in obese patients often shows dismal prognosis and resistance to immune checkpoint blockade (ICB) therapy. The molecular mechanism for these phenomena is largely unknown. Here we show that obese visceral adipose tissues (VAT) can talk to distant PDAC by delivering their 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 extra pseudouridines from RNA cleavage. Pseudouridines released from cancer cells activate mast cells which inhibit CD8+ T cell activity, forming an immunosuppressive tumor microenvironment which enhances cancer progression and resistance to ICB. We also demonstrate the harmful effects of VAT-EV CTSA-pseudouridine-mast cell axis for PDAC in obese patients. Animal experiments indicate that Ctsa knockdown effectively enhances the 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.