Dietary -mangostin triggers immunogenic cell death and activates cGAS signaling in acute myeloid leukemia

Immunogenic cell death (ICD), one of cell-death types through release of damage-associated molecular patterns from dying tumor cells, activates tumor-specific immune response and elicits anti-tumor immunity by traditional radiotherapy and chemotherapy. However, whether natural products could induce ICD in leukemia is not elucidated. Here, we report dietary gamma-mangostin eradicates murine primary leukemic cells and prolongs the survival of leukemic mice. As well, it restrains primary leukemic cells and CD34(+) leukemic progenitor cells from leukemia patients. Strikingly, gamma-mangostin attenuates leukemic cells by inducing ICD as characterized by expression of HSP90B1, ANXA1 and IL1B. Additionally, gamma-mangostin accelerates cytoplasmic chromatin fragments generation, promoting DNA damage response, and enhances cGAS activation, leading to up-regulation of chemokines. Meanwhile, it induces HDAC4 degradation and acetylated histone H3 accumulation, which promotes chemokines transcription. Ultimately, CD8(+) T cell is activated and recruited by gamma-mangostin-induced chemokines in the microenvironment. Our study identifies gamma-mangostin triggers ICD and activates cGAS signaling through DNA damage response and epigenetic modification. Therefore, dietary gamma-mangostin would act as a potential agent to provoke anti-tumor immunity in the prevention and treatment of leukemia.