Abstract
Breast cancer (BC) represents the most common malignancy among women worldwide. Immune evasion serves as a critical factor for treatment resistance and recurrence metastasis. For USP38, a member within deubiquitinating enzyme family, its expression pattern, biological function, and regulatory mechanism on tumor immune microenvironment in BC lacked systematic investigation. TIMER and UALCAN databases were used to analyze USP38 expression profile. Forty pairs BC tissue and cell lines were collected for validation. Knockdown/overexpression models were constructed. CCK-8, Transwell, co-immunoprecipitation, ubiquitination analysis, CD8 + T cell co-culture, and in vivo tumor‑bearing experiments were employed to explore function and mechanism. USP38 was highly expressed in BC tissues and cells. USP38 knockdown inhibited proliferation, migration, and invasion. Mechanistically, USP38 directly bound PD-L1 and removed its ubiquitination modification, enhancing PD-L1 stability. USP38 knockdown activated CD8 + T cell function, promoted IFN-γ and granzyme B secretion, and enhanced anti-tumor immunity. In vivo USP38 knockdown suppressed tumor growth, whereas PD-L1 overexpression reversed this effect. USP38 stabilizes PD-L1 through deubiquitination, inhibits CD8 + T cell-mediated anti-tumor immunity, and promotes immune evasion and malignant progression in BC.