Development and Validation of a Six-Gene Signature of Myeloid Antigen Presentation Dysfunction Based on Single-Cell and Multi-Cohort Transcriptomics for Predicting Prognosis and Recurrence of Hepatocellular Carcinoma

BACKGROUND: Myeloid antigen-presentation dysfunction is a central but incompletely translated immune state in hepatocellular carcinoma (HCC). This study aimed to develop a compact prognostic and recurrence model directly anchored in single-cell-defined myeloid antigen-presentation loss. METHODS: In this prognostic prediction-model development and validation study, GSE149614 was used as the single-cell discovery cohort. Tumor and normal myeloid cells were extracted, antigen-presentation (AP) module scores were calculated, and AP-loss candidate genes were identified using pseudobulk aggregation. Candidate genes were projected to TCGA-LIHC, GSE14520, and GSE76427 bulk transcriptomic cohorts. Survival-oriented model refinement was performed in GSE14520 using overall survival (OS) and recurrence-free survival (RFS), followed by validation with Kaplan-Meier analysis, Cox regression, fixed-time AUC, clinicopathological comparison, pathway scoring, targeted cell-cell communication analysis, and nomogram construction. RESULTS: A total of 13,784 myeloid cells were analyzed, including 8,209 tumor-infiltrating myeloid cells and 5,575 normal myeloid cells. Tumor-associated myeloid cells showed lower AP scores than normal myeloid cells (P = 0.04054). A compact six-gene signature consisting of SMOX, CSF1, AQP9, FLNB, COL7A1, and MXI1 was established. In GSE14520, the signature predicted poor OS (HR = 1.94, 95% CI: 1.41-2.65, P = 3.73e-05) and poor RFS (HR = 1.60, 95% CI: 1.23-2.08, P = 4.63e-04). In TCGA-LIHC, it also predicted inferior OS (HR = 1.49, 95% CI: 1.12-1.99, P = 5.83e-03). High-risk tumors showed enhanced glycolysis, hypoxia, epithelial-mesenchymal transition (EMT), angiogenesis, and IL6-JAK-STAT3 activity, with reduced antigen-presentation and IFNG response signals. CONCLUSIONS: We report a compact single-cell-derived myeloid AP-loss signature for HCC prognosis and recurrence stratification. The model links clinical risk to a biologically interpretable myeloid dysfunction state and broader tumor microenvironment remodeling.