Abstract B044: USP27X plays a crucial role in controlling the cancer cell growth and shaping the tumor immune microenvironment

Abstract Programmed cell death ligand 1 (PD-L1) is crucial for cancer immune evasion as it suppresses T-cell activation and function and acts as a checkpoint for anti-cancer immunity. Excessive PD-L1 level on tumor cells delays T-cell-mediated cytotoxicity by interacting with PD-1 on tumor-infiltrating lymphocytes (TILs). As a result, PD-L1 has become a key target in anti-cancer immunotherapy. Recent studies have highlighted the significant impact of post-translational modifications of PD-L1, such as ubiquitination, phosphorylation, and glycosylation, on immune escape and suppression. Recent findings suggest that deubiquitinating enzymes (DUBs) are involved in PD-L1 deubiquitination. However, the specific DUBs critical for PD-L1 stabilization in cancer cells and the role of this process in PD-L1 stabilization remain unclear. Therefore, investigating the molecular mechanism underlying PD-L1 stability in tumors will provide new means to enhance the effectiveness of PD-L1 blockade in a clinical setting. Previous research from our laboratory has revealed that ubiquitin-specific protease 27X (USP27X), a DUB essential for tumor growth, regulates the steady-state levels of key proteins for tumor growth, such as CCND1 and EGFR in cancer cells. Ablation of USP27X hinders xenograft tumor growth and increases the sensitivity to targeted therapy. Our current study aims to determine the impact of USP27X ablation in cancer cells on the tumor microenvironment and tumor development. Here, we identify USP27X as a critical regulator of PD-L1 stability and immune suppression in lung cancer. In-vitro studies revealed that USP27X interacts with PD-L1 and stabilizes it. Knockdown of USP27X resulted in rapid PD-L1 degradation, which was further rescued by proteasome inhibition. In-vivo studies showed that loss of USP27X increased the immune cell infiltration along with the cytokine and chemokine. Additionally, immunohistochemistry of USP27X-deficient tumors also confirmed reduced PD-L1 level and enhanced T-cell infiltration. This study sheds light on the potential of targeting USP27X as a novel strategy to destabilize PD-L1, enhance anti-tumor immunity, and improve the efficacy of immunotherapies. Citation Format: Satyam Singh, Shamshad Alam, Boyko S. Atanassov. USP27X plays a crucial role in controlling the cancer cell growth and shaping the tumor immune microenvironment [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr B044.