Development and validation of an immune‐related prognosis signature associated with hypoxia and ferroptosis in hepatocellular carcinoma

Abstract Background Hypoxia and ferroptosis are crucial in the occurrence and development of hepatocellular carcinoma (HCC), and they both affect the immune status of the tumor microenvironment. Previous studies have also shown a link between hypoxia and ferroptosis. Patients and methods In all, 814 HCC cases from The Cancer Genome Atlas and Gene Expression Omnibus databases were used as the discovery cohort, and 230 HCC cases from the International Cancer Genome Consortium database were used as the validation cohort. Hypoxia subtypes and ferroptosis subtypes were identified by consensus cluster analysis according to 174 hypoxia‐related genes and 193 ferroptosis‐related genes. The prognostic signature was constructed using the Cox and LASSO regression analyses, and two risk groups were identified. A comprehensive analysis of the clinical and immune characteristics between the two risk groups was further performed. Results Two hypoxia subtypes and two ferroptosis subtypes were distinguished and verified; subsequently, a five‐gene prognostic signature was constructed and the risk score could be acquired by the following formula: risk score = 0.0604*Expression (CA9)−0.0714*Expression (ANXA10) + 0.1501*Expression (CDC20)−0.0853*Expression (CYP7A1) + 0.0530*Expression (SPP1). Compared with the low‐risk group, the high‐risk group had a worse prognosis. The high‐risk group also showed a higher level of immune infiltration than the low‐risk group, and immune checkpoints were generally upregulated in the high‐risk group. The antigen presentation ability of the low‐risk group was poor, which may be related to the immune escape mechanism. Drug sensitivity analysis indicated that the high‐ and low‐risk groups were sensitive to tyrosine kinase inhibitors and chemotherapeutic drugs, respectively. Conclusion The hypoxia‐, ferroptosis‐, and immune‐associated prognostic signature we constructed could stratify patients with HCC and guide precise treatment.