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This study aims to uncover the underlying mechanism by which PCSK9 promotes hepatocellular carcinoma (HCC) immune escape and to explore potential intervention strategies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Co-culture assay assessed the cytotoxicity of CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cells against PCSK9-knockout HCC cells. Hepa1-6, H22, and HepG2 cells were used to establish HCC mouse models. Tumor microenvironment changes were evaluated using flow cytometry and single-cell RNA sequencing. Additionally, we developed a CRISPR adenine base editing (ABE) base editor and screened small molecule inhibitors for PCSK9 inhibition in HCC treatment.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      We found that PCSK9 was highly expressed and correlated with poor survival in patients with HCC. While PCSK9 deficiency did not affect HCC growth in vitro, it significantly enhanced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T cell-mediated selective killing in vitro and in vivo. This selective killing of PCSK9-deficient HCC cells could not be explained by existing theories related to major histocompatibility complex-I and T-cell receptor (TCR) degradation. Instead, our study revealed that PCSK9 knockout inhibited the expression of secreted phosphoprotein 1 (SPP1) and programmed death-ligand 1 (PD-L1) in HCC cells, and identified friend leukemia virus integration 1 (FLI1) as their co-transcription factor. Overexpression of FLI1 reversed the PCSK9 knockout-induced downregulation of SPP1 and PD-L1, thereby promoting HCC immune escape. Furthermore, PCSK9 upregulated FLI1 expression through the neurogenic locus notch homolog protein 3 (NOTCH3) pathway. Additionally, we designed an all-in-one ABE base editor with thyroxine-binding globulin promoter (ABE-TBG-PCSK9) to knock down PCSK9 and identified parecoxib as a small molecule inhibitor. We confirmed both approaches enhanced CD8\n                      <jats:sup>+<\/jats:sup>\n                      T-cell antitumor activity, significantly inhibiting HCC tumor growth and prolonging mouse survival.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>PCSK9 promoted HCC immune escape by upregulating SPP1 and PD-L1 via NOTCH3\/FLI1 signaling. CRISPR ABE-mediated PCSK9 deficiency and PCSK9 inhibitor parecoxib may serve as effective strategies to inhibit HCC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2025-012586","type":"journal-article","created":{"date-parts":[[2025,11,28]],"date-time":"2025-11-28T20:35:17Z","timestamp":1764362117000},"page":"e012586","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":5,"title":["Blocking PCSK9 suppresses hepatocellular carcinoma immune escape by decreasing FLI1-mediated SPP1 and PD-L1 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