Cancer cells evade the immune system by expressing inhibitory immune checkpoint receptors such as ecto-5’-nucleotidase (NT5E), also known as CD73, which consequently suppress tumor neoantigen-specific immune response. Blockade of CD73 in mouse models of breast cancer showed a reduction in tumor growth and metastasis. CD73 expression is elevated in a variety of human tumors including breast cancer. While the regulation of CD73 expression at the transcriptional level has been well understood, the factors involved in regulating CD73 expression at the post-transcriptional level have not been identified. Herein, we discovered that the ubiquitin-specific peptidase 22 (USP22), a deubiquitinase associated with poor prognosis and overexpressed in breast cancers, is a positive regulator for CD73. Targeted USP22 deletion resulted in a statistically significant reduction in CD73 protein expression. In contrast, CD73 mRNA expression levels were not reduced, but even slightly increased by USP22 deletion. Further analysis demonstrated that USP22 is a deubiquitinase that specifically interacts with and inhibits CD73 ubiquitination. Consequently, USP22 protects CD73 from ubiquitin-mediated proteasomal degradation in breast cancer cells. Targeted USP22 deletion, inhibits syngeneic breast cancer growth. Collectively, our study reveals USP22 as a positive regulator to promote CD73 expression in breast cancer and provides a rationale to target USP22 in antitumor immune therapy.