Abstract B028: Dual Oncotargeting and Immunotherapeutic Potential of USP22 Inhibition Across Diverse Human Cancers

Abstract Immune checkpoint blockade (ICB) therapy has transformed cancer treatment by mobilizing the immune system to recognize and eliminate malignant cells. However, a significant proportion of patients display either primary resistance—failing to respond from the outset—or acquired resistance, characterized by relapse after an initial benefit. Understanding and overcoming these resistance mechanisms remains a major challenge in oncology. Ubiquitin-specific peptidase 22 (USP22) was initially identified as one of the 11 genes in the "death-from-cancer" signature and is strongly associated with poor clinical outcomes across multiple malignancies, including triple-negative breast cancer (TNBC) and lung cancer. Our group and others have demonstrated that USP22 functions as a potent oncogene by blocking apoptosis and promoting cell cycle progression (Mol. Cell, 2012; Cell Discovery, 2015). Furthermore, we showed that USP22 maintains TNBC stemness and that its genetic deletion significantly reduces tumor growth and lung metastasis (Science Advances, 2024; Cancer Letters 2024; iScience, 2024). In addition to its oncogenic role, USP22 plays a critical function in immune regulation. Our previous studies identified USP22 as a FoxP3-specific deubiquitinase essential for regulatory T cell (Treg) suppressive function. Mice with Treg-specific USP22 deletion exhibited vigorous tumor rejection without overt autoimmunity, revealing its role in maintaining an immunosuppressive tumor microenvironment (Nature, 2020; Science Advances, 2022). Moreover, USP22 contributes to immune evasion by upregulating immunoinhibitory ligands such as PD-L1 and CD73, both of which dampen antitumor immune responses. Our recent unpublished data further uncover USP22 as a negative regulator of MHC-I expression across multiple murine and human tumor models. Inhibition of USP22 significantly enhanced MHC-I presentation and boosted CD8+ T cell–mediated cytotoxicity. These findings position USP22 at the intersection of tumor-intrinsic growth and immune suppression. Capitalizing on these insights, we developed the first-in-class USP22-specific small molecule inhibitor. The second-generation compound exhibits potent antitumor activity across a broad range of cancer models with minimal toxicity. We are currently performing IND-enabling studies and preparing for a first-in-human Phase 1 clinical trial in patients with advanced TNBC. Collectively, these findings establish USP22 as a dual-modality therapeutic target that drives tumor progression while simultaneously suppressing antitumor immunity. Targeting USP22 offers a promising strategy to overcome resistance to ICB and improve clinical outcomes across diverse cancer types. Citation Format: Kun Liu, William J. Gradisha, Huiping Liu, Deyu Fang. Dual Oncotargeting and Immunotherapeutic Potential of USP22 Inhibition Across Diverse Human Cancers [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr B028.