PD-1 (CD279)–PD-L1 (CD274) inhibitory signaling is critical for cancer immune evasion, and thus has become one of the major targets in anticancer immunotherapy. There are several studies that demonstrate the potent effects of posttranslational modifications of CD274 on immune inactivation and suppression, such as ubiquitination, phosphorylation, glycosylation, and palmitoylation. However, the regulatory mechanisms for CD274 deubiquitination are still largely unclear. Here, we identified ubiquitin-specific protease 22 (USP22) as a novel deubiquitinase of CD274. USP22 directly interacted with the C terminus of CD274, inducing its deubiquitination and stabilization. Across multiple cancer types, USP22 was highly expressed and frequently altered in liver cancer, closely correlating with poor prognosis of these patients. Genetic depletion of USP22 inhibited liver cancer growth in an immune system–dependent manner, increased tumor immunogenicity and tumor-infiltrating lymphocytes, and improved therapeutic efficacy of CD274-targeted immunotherapy and CDDP-based chemotherapy in mice. We demonstrate that targeting USP22 is a promising strategy to potentiate anticancer immunity for CD274-amplified cancer.