Bcl6 drives stem-like memory macrophages differentiation to foster tumor progression

Cancer development is a long-lasting process during which macrophages play a pivotal role. However, how macrophages maintain their cellular identity, persistence, expanding and pro-tumor property during malignant progression remains elusive. Inspired by the recent report of the activation of stem cell-like self-renewal mechanism in mature macrophages, we postulate that intra-tumoral macrophages might be trained to assume stem-like properties and memory-like activity favoring cancer development. Herein we demonstrated that tumor infiltrating macrophages rapidly converted into the CD11b⁺F4/80⁺Ly6C^-Bcl6⁺ phenotype, and adopted stem cell-like properties involving expression of stemness-related genes, long-term persistence and self-renewing. Importantly, Bcl6⁺ macrophages stably maintained cell identity, gene signature, metabolic profile, and pro-tumor property even after long-term culture in tumor-free medium, which were hence termed stem cell-like memory macrophages (SMMs). Mechanistically, we showed that transcriptional factor Bcl6 co-opted the demethylase Tet2 and the deacetylase SIRT1 to confer the epigenetic imprinting and mitochondrial metabolic traits to SMMs, bolstering the stability and longevity of trained immunity in tumor-associated macrophages (TAMs). Furthermore, tumor-derived redHMGB1 was identified as the priming signal, which, through TLR4 and mTOR/AKT pathway, induced Bcl6-driven program underpinning SMMs generation. Collectively, our study uncovers a distinct macrophage population with a hybrid of stem cell and memory cell properties, and unveils a regulatory mechanism that integrates transcriptional, epigenetic and metabolic pathways to promote long-lasting pro-tumor immunity.