From Pan-Cancer Transcriptomics to Trial Alignment: Systematic Prioritization of PCSK9-Targeted Oncology Indications

Proprotein convertase subtilisin/kexin type 9 (PCSK9) governs low-density lipoprotein receptor (LDLR) degradation, yet whether this cholesterol-regulating convertase intersects with tumor immunity remains incompletely defined. We integrated pan-cancer transcriptomics, single-cell and spatial transcriptomics, network biology, immune deconvolution, in silico perturbation, and structural drug validation to dissect PCSK9 function across tumors. Across 33 TCGA cancer types, PCSK9 was selectively up-regulated in digestive tract tumors (COAD log2FC = 2.71, FDR = 4.39 x 10^-18) and enriched for cholesterol metabolism, proliferation, and interferon-response programs. Immune deconvolution of 6,325 tumors revealed positive correlations with macrophages, Tregs, and MDSCs and negative correlations with CD8 + T cells, with PCSK9-high tumors showing an immune-excluded phenotype (TIDE rho = -0.46, P < 2.2 x 10^-16) and higher predicted immunotherapy response. Single-cell analysis of 71,914 cells from three HCC cohorts resolved PCSK9 as hepatocyte-restricted (18.54% positive) and tumor-up-regulated. PCSK9-high hepatocytes adopted an M2-dominant polarization, rewired intercellular communication, occupied a de-differentiated state, and revealed FGL1 as a core downstream node with dose-dependent Notch activation via a conserved NOTCH3 axis. Spatial transcriptomics confirmed PCSK9-macrophage co-localization and co-expression of FGL1, JAG2, and CD276. Drug screening and 100 ns molecular dynamics simulation nominated palbociclib (RMSD = 1.54 ± 0.25 A) as a direct PCSK9 binder and simvastatin as an indirect pathway modulator. Collectively, PCSK9 emerges as a metabolism-immunity crossover modulator whose tumor-cell-intrinsic expression orchestrates an immunosuppressive microenvironment, providing a multi-omics rationale for PCSK9-targeted therapy in digestive tract malignancies.