Targeting PSMD14 enhances immunotherapy efficacy by promoting PD-L1 degradation and reshaping the tumor microenvironment in breast cancer.

BACKGROUND

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have shown encouraging clinical efficacy in breast cancer, primarily by modulating the tumor microenvironment (TME). However, achieving durable clinical responses remains a major challenge. Although the deubiquitinating enzyme 26S proteasome non-ATPase regulatory subunit 14 (PSMD14) is known to exert oncogenic functions in various cancers, its potential role in regulating tumor immune evasion remains unclear. This study investigates how PSMD14 regulates PD-L1 and reshapes the TME, with the goal of clarifying its impact on immune regulation in breast cancer.

METHODS

PSMD14 expression and its prognostic significance in breast cancer were analyzed using public databases and clinical samples. The correlation between PSMD14 and PD-L1 was validated by immunohistochemistry (IHC), western blot, and flow cytometry. The mechanism by which PSMD14 stabilizes PD-L1 through deubiquitination and their interaction was investigated using cycloheximide chase assays, co-immunoprecipitation (Co-IP), and ubiquitination assays. The impact of PSMD14 on the TME and its influence on immunotherapy efficacy were evaluated using T cell cytotoxicity assays, syngeneic mouse models, and flow cytometry analyses.

RESULTS

PSMD14 was highly expressed in breast cancer and correlated with poor patient prognosis. Mechanistically, PSMD14 stabilized PD-L1 by interacting with its intracellular domain and removing its K48-linked polyubiquitin chains, thereby inhibiting proteasomal degradation. Inhibition of PSMD14 enhanced antigen presentation and CD8⁺ T cell activation, reduced the accumulation of regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs), and altered macrophage polarization. These changes collectively improved the response to immunotherapy in breast cancer.

CONCLUSION

This study identifies PSMD14 as a critical regulator of immune responses in breast cancer. Targeting PSMD14 enhances the effectiveness of immunotherapy by promoting PD-L1 degradation and remodeling the TME, offering a potential strategy to improve clinical outcomes.