Precision oncology has emerged as a groundbreaking framework in cancer treatment, leveraging detailed molecular characterization to develop tailored therapeutic strategies. Extending our earlier findings on ISG15’s contribution to the development of pancreatic cancer stem cells (CSCs), the present study uncovered simultaneous overexpression of ISG15 and HMGCR in pancreatic ductal adenocarcinoma (PDAC). Combined inhibition of these two targets produced a synthetic lethal effect, resulting in efficient CSC depletion and substantial hindrance of tumor development. To harness this cooperative vulnerability, we constructed a hyaluronic acid-coated liposomal nanocarrier (LNP-Kd/Statin) that simultaneously delivers ISG15-specific siRNA and statins that block HMGCR activity. At the molecular level, ISG15 physically associates with HMGCR; its reduction prevents K48-linked ubiquitin-mediated proteasomal breakdown of HMGCR in an ISGylation-independent manner. This stabilization elevates cholesterol levels to promote cell viability while concurrently diminishing essential biosynthetic intermediates, thereby sensitizing the cells. Comprehensive sterolomics analysis validated the resulting metabolic shift, directly connecting the breakdown of cholesterol homeostasis to CSC eradication. Collectively, these insights illuminate a previously unrecognized ISG15-HMGCR signaling axis that drives PDAC progression and introduce a nanotechnology-based platform for undermining cancer stemness by exploiting metabolic liabilities. The approach strengthens the clinical applicability of synthetic lethality concepts in precision oncology, particularly for refractory solid tumors.
