Metabolic rewiring of macrophages by CpG potentiates clearance of cancer cells and overcomes tumor-expressed CD47-mediated ‘don’t eat me signal’.

Macrophages enforce anti-tumor immunity by engulfing and killing tumor cells. Although these functions are determined by a balance of stimulatory and inhibitory signals, the role of macrophage metabolism is unknown. Here, we study the capacity of macrophages to circumvent inhibitory activity mediated by CD47 on cancer cells. We show that stimulation with CpG, a TLR9 agonist, evokes changes in the central carbon metabolism of macrophages that enable anti-tumor activity, including engulfment of CD47(+) cancer cells. CpG activation engenders a metabolic state, that requires fatty acid oxidation and shunting of tricarboxylic acid cycle intermediates for de novo lipid biosynthesis. This integration of metabolic inputs is underpinned by carnitine palmitoyltransferase 1A and ATP citrate lyase, which together, impart macrophages with anti-tumor potential capable of overcoming inhibitory CD47 on cancer cells. Our findings identify central carbon metabolism to be a novel determinant and potential therapeutic target for stimulating anti-tumor activity by macrophages.