Bcl6 Drives Stem-Like Memory Macrophages Differentiation by Coordinating Transcriptional and Metabolic Programs

Innate immunological memory or trained immunity is increasingly recognized, but fundamental issues regarding specific signals and mechanisms driving trained immunity, particularly in tumor setting, remain largely unknown. Our study indicates that acute tumor priming induced development of CD11b+F4/80+Ly6C-PD-L1+Bcl6+ macrophage subset, which was characterized by stem signature genes, long-term persistence, self-renewing, and pro-tumor memory, and therefore termed stem-like memory macrophages (SMMs). The transcription factor Bcl6, controlled by mTOR, orchestrated transcriptional and metabolic pathways to drive SMMs generation while excluding alternative cell fate choice. Moreover, Bcl6 co-opts the demethylase Tet2 to confer epigenetic marks to stem- and lineage-related genes, ensuring longevity and stability of trained immunity. Finally, tumor-derived reduced HMGB1 served as the priming signal through TLR4 and PI3-K/AKT pathway to initiate trained program in macrophages. Together, our study identifies a macrophage subset with a hybrid of stem and memory cells status and unveils an unappreciated regulatory circuitry controlling memory macrophages development.