Growth differentiation factor 11 reprograms M2-like macrophages: Targeting immunometabolism for cancer therapy

. Their study revealed that growth differentiation factor 11 (GDF11) functions as a potent, non-cytotoxic immunometabolic modulator within the tumor microenvironment. GDF11 treatment initiates an intense reprogramming in pro-tumoral M2-like macrophages by activating the Smad2/3 pathway and driving a fundamental shift in cellular identity. This reversal is highlighted by the significant downregulation of the M2 marker cluster of differentiation 206 and critical metabolic restructuring, including enhanced mitochondrial function (increased oxygen consumption rate), decreased total cellular cholesterol content, and a necessary increase in reactive oxygen species production. This work uniquely positions GDF11 as a dual-axis therapeutic agent, capable of both direct tumor inhibition and immunometabolic reprogramming of M2-like macrophages, yielding a re-educated secretome that effectively suppresses the pro-proliferative and migratory capacity of hepatocellular carcinoma cells. It suggests GDF11 may be a promising, mechanism-based therapeutic strategy for simultaneously managing the progression of a subset of malignancies and resolving the underlying chronic inflammatory and metabolic disorders associated with M2-like macrophage dysfunction.