Hypoxia is a representative feature of the TME, and hypoxia increases the transcription of ubiquitin-specific protease 22 (USP22) by activating hypoxia-inducible factor-1α (HIF-1α), a key component in stemness maintenance, thereby causing HIF-1α/USP22 positive feedback to repress TP53 expression and stabilize cancer stemness in HCC [22]. The gene discussed is HIF1A; the disease is hepatocellular carcinoma.