A Hypoxia and EMT-Related Gene Signature for Predicting Prognosis and Immunotherapy Benefit in Hepatocellular Carcinoma

Abstract

Objective Epithelial-mesenchymal transition (EMT) and hypoxia are key factors in hepatocellular carcinoma (HCC) metastasis and recurrence. This study explored their combined impact on HCC prognosis and immunotherapy benefit. Methods TCGA, ICGC, and GEO (GSE14520) datasets were analyzed. An EMT-hypoxia prognostic model (EHPM) was built using LASSO, trained on TCGA (n = 365) and validated in ICGC (n = 231) and GSE14520 (n = 221). ROC curves assessed accuracy. ssGSEA and TIDE explored EHPM–tumor immune microenvironment relationships and predicted immunotherapy benefit. Nine EMT/hypoxia-related genes were validated by qRT-PCR in eight paired HCC and adjacent normal liver tissues. Results The 9-gene EHPM was stable across cohorts. The 1-, 2-, and 3-year AUCs were 0.82, 0.72, and 0.76 in TCGA; 0.717, 0.701, and 0.651 in ICGC; and 0.681, 0.609, and 0.557 in GEO. High-EHPM patients showed advanced TNM stage (p = 0.003), poorer differentiation (p = 0.003), higher vascular invasion (p = 0.002), elevated AFP (p < 0.001), shorter overall survival (TCGA and ICGC: p < 0.0001; GEO: p = 0.013), and immunosuppression. EHPM was an independent prognostic factor (HR = 3.315, 95% CI 2.501–4.215, p < 0.001). TIDE indicated more immune non-responders in the high-EHPM group (p < 7.9e-07), As this is based on computational inference rather than treated patients, it should be regarded as hypothesis-generating. The nomogram predicted OS with AUCs of 0.825, 0.734, and 0.777 at 1, 2, and 3 years. qRT-PCR confirmed upregulation of all nine genes in HCC tissues. Conclusion This EMT-hypoxia model effectively predicts OS and may help identify HCC patients likely to benefit from immunotherapy, though this requires validation in ICI-treated cohorts.