Pseudo-starvation induced by Bam15 uncoupler aggravates tumor metabolic stress and enhances antitumor immunity

Metabolic inhibitors present as promising strategies to starve tumor. However, whether the metabolic changes they induced could overcome immunoresistance in the tumor micro-environment and lead to long-term energy restriction was unwarranted. By using mitochondrial uncoupler Bam15, we demonstrate that the selective invalid consumption of mitochondrial potential induces tumor starvation and enhances anti-tumor activity of T cells and macrophages. Bam15 administration in tumor-bearing mice reveals a reprogrammed metabolic profile characteristic of increasing pentose phosphate pathway but decreasing biosynthetic pathways, and the induced aberrant metabolites responded to mitochondrial enzymes lead to markedly upregulation of toxic T-cells. Simultaneously, pro-tumor macrophage undergoes significant modifications by transforming metabolic patterns, increasing anti-inflammatory factors and inhibiting migration-promoting genes. Further, targeted delivery of Bam15 via T lymphocyte-derived cellular vesicles (TCV) blocks immune checkpoint functions and strongly inhibits tumor progression in vivo. Bam15 therefore establishes a previously unidentified pro-metabolic starvation tumor therapy based on ATP restriction and immune activation.