The Role of UBR2 in Triple-Negative Breast Cancer and Its Implications for Immune Checkpoint Blockade Therapy

Objective UBR2 (also referred to as n-recognin 2, the E3 component of ubiquitin protein ligase) targets proteins with unstable N-terminal residues for polyubiquitination and proteasome-mediated degradation. It was initially identified as a crucial oncogene during embryonic development. Nevertheless, the function of UBR2 in triple-negative breast cancer (TNBC) and its non-ubiquitination role, particularly in suppressing antitumor immune responses, remain elusive. Methods Utilizing bulk RNA and single-cell RNA sequencing datasets from the GEO and TCGA databases, differentially expressed genes (DEGs) were discerned. Moreover, the relationship between UBR2 and PD-L1 was verified via overexpression viruses, shRNA viruses, and Western blotting. In addition, the correlation between UBR2 and immunotherapy was investigated by means of flow cytometry and immune-infiltration analysis in both in vivo and in vitro experiments. Results In the cohort of TNBC patients presenting an immune desert microenvironment, as well as in the group of patients responding poorly to PD-L1/PD-1 therapy, UBR2 exerted a significant impact on the establishment of an immunosuppressive microenvironment. The inhibition of UBR2 could diminish the expression of PD-L1 in TNBC cell lines. In addition, the expression level of UBR2 could act as a potential indicator for PD-L1 therapy in TNBC patients, where higher UBR2 expression suggests greater responsiveness to PD-L1 therapy. Concurrently, we screened for inhibitors (11-oxo-mogroside V) targeting the functional domain of UBR2, and concurrent inhibition of UBR2 in combination with PD1 therapy can reduce the tumor burden in TNBC. Conclusion Our findings indicate that the inhibition of UBR2 can augment TIL infiltration by diminishing PD-L1 expression, thereby emerging as an efficacious strategy (the functional inhibitors of UBR2) to enhance the therapeutic efficacy of PD-L1/PD1 blockers, offering a novel perspective for the treatment of TNBC through combined immunotherapy.