Repression of the stress granule protein G3BP2 inhibits immune checkpoint molecule PD-L1

Mounting evidence suggests that cancer stemness and immunosuppression are related, but the underlying mechanisms behind these are not clear. We previously reported that the stress granule-associated protein G3BP2 is involved in the regulation of tumor-initiating (stem) cells. In this study, we show that this protein also upregulates the immune checkpoint molecule PD-L1 under conditions of stress in breast and glioblastoma cancer cells, revealing a previously unknown connection between stemness programs, stress responses, and immune checkpoint control. We also identified a significant correlation between G3BP2 and PD-L1 co-expression in tumor tissues from cancer patients. To assess the targetability of G3BP2, we employed a small molecule (C108) that binds G3BP2 and interferes with the stress response. Tumors treated with C108 had increased CD8 T-cell proliferation and infiltration. Moreover, treatment of breast tumor-bearing mice with C108 resulted in a significant survival benefit and long-term cures. Cancer cells treated with C108 or cancer cells with genetically repressed G3BP2 had decreased PD-L1 expression due to enhanced mRNA degradation. Our study provides a compelling mechanism linking stress granule formation and immune checkpoint program of cancer, suggesting this link may provide new opportunities for improving anticancer immunotherapy.