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 PD-L1 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.