Conventional treatments like chemotherapy and radiotherapy frequently provoke anti-tumor immunity by initiating immunogenic cell death (ICD), a process where expiring cancer cells extrude damage-associated molecular patterns to stimulate targeted immune reactions. Despite this, the capacity of natural compounds to precipitate ICD within leukemic contexts remains largely unexplored. The present investigation demonstrates that the dietary compound γ-mangostin successfully eliminates primary murine leukemic populations, thereby extending the lifespan of affected mice. Furthermore, this agent effectively suppresses primary malignant cells alongside $CD34^+$ leukemic progenitor cells derived from human patients. Notably, the anti-leukemic effects of γ-mangostin are mediated via ICD induction, confirmed by the marked expression of IL1B, ANXA1, and HSP90B1. Moreover, the compound expedites the formation of cytoplasmic chromatin fragments, which subsequently drives the DNA damage response and augments cGAS pathway activation, ultimately elevating chemokine levels. In parallel, γ-mangostin precipitates HDAC4 degradation while fostering the buildup of acetylated histone H3, mechanisms that jointly facilitate the transcription of chemokines. As a result, these elevated chemokines recruit and activate $CD8^+$ T cells within the local microenvironment. Ultimately, our findings reveal that γ-mangostin initiates ICD and engages cGAS networks via a combination of epigenetic alterations and the DNA damage response. Consequently, incorporating dietary γ-mangostin offers a promising pharmacological strategy for stimulating immune-mediated defenses in the clinical management and prophylaxis of leukemia.
