Mechanistically, we show that PRSS35 is a potent secreted protease activated by PC cleavage and, through its substrate CXCL2, PRSS35 suppresses HCC progression in vivo via inhibition of CXCL2-mediated neutrophil recruitment and NETs formation (Supplementary Fig. 4p). Here, PRSS35 is linked to hepatocellular carcinoma.