A heparanase-specific LYTAC degrader reinforces natural killer cell cytotoxicity within the tumor microenvironment

Highlights•A nonproteinogenic compound-conjugated LYTAC degrader•Specific inhibition of the extracellular heparanase with minimal toxicity•An organic molecule to manipulate the tumor microenvironment•Promotion of the treatment of natural killer (NK) cells for HCC in vitro and in vivoSummaryHepatocellular carcinoma (HCC) evades immune surveillance by natural killer (NK) cells through the secretion of heparanase (HPA1), which cleaves side chains of heparan sulfate (HS) on the surface of HCC, promoting an immunosuppressive tumor microenvironment (TME). However, developing specific inhibitors for secreted HPA1 remains challenging. Given the pioneering lysosome-targeting chimera (LYTAC) strategy for degrading extracellular proteins, we have developed a nonproteinogenic compound-conjugated LYTAC degrader named JW-9 to specifically target and degrade extracellular HPA1. With its small size and avoidance of antigen-binding site variability, LYTAC JW-9 effectively degrades HPA1 with minimal toxicity, leading to an increased abundance of natural cytotoxicity receptor (NCR) ligands on HCC cells. Importantly, LYTAC JW-9 significantly enhances the anti-tumor activity of NK cells against primary HCC cells both in vitro and in vivo. The findings suggest that the heparanase-specific LYTAC degrader offers a promising approach for modulating the TME and has the potential to enhance clinical NK cell-based immunotherapy.