LAUSR

Significance PD-L1 is well known as an immune checkpoint molecule, which suppresses immune surveillance through binding to its receptor PD-1. Intracellular PD-L1 can also protect messenger RNAs of several DNA damage repair–related genes from degradation and enhance tumor resistance to DNA-damaging therapy. Triple-negative breast cancer (TNBC) has the worst prognosis and highest risk of distant relapse in breast cancer and shows resistance to immunotherapy and radiotherapy. In this study, we found that D-mannose can promote the degradation of PD-L1 and significantly enhance immunotherapy and radiotherapy of TNBC. Since TNBC treatment is still a clinical challenge, our findings provide strategies to enhance the therapeutic efficacy of TNBC and may have clinical application. Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose–mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose–induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair–related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.