Overall, a comprehensive bioinformatics analysis of hypoxia-induced PD-L1 inhibitor resistance in HCC was performed and revealed that genes such as TPX2, NDC80, POLE2, GABARAPL1, and PIK3R1 may be involved in the PI3K-AKT signaling pathway and play an essential role in the pathological and physiological processes of hypoxia-induced PD-L1 inhibitor resistance. Here, TPX2 is linked to hepatocellular carcinoma.