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

Table 1 Growth differentiation factor 11-mediated key immunometabolic mechanisms on M2-like macrophages

Feature/mechanism	M2-like macrophage state (baseline)	GDF11 treatment effect	Proposed anti-tumoral impact	Molecular markers/processes
Phenotype	Pro-tumoral, immune-suppressive	Reversal/de-polarization	Loss of pro-tumoral function and recognition	CD206 (decrease); anti-tumoral phenotype (increase)
Signaling	Varied/dependent on TME	Activation of canonical pathway	Transduction of immunometabolic shift signal	Smad2/3 activation
Mitochondria/energy	Low OXPHOS, high glycolysis	Restoration of OXPHOS	Enhanced energy metabolism for microbicidal function	Oxygen consumption rate (increase)
Lipid metabolism	High cholesterol/lipid accumulation	Reduction of lipid content	Interference with M2 maintenance and signaling	Total cellular cholesterol (decrease)
Redox state	Low microbicidal ROS	Increase in ROS	Induction of cytotoxic/inflammatory state	Reactive oxygen species (increase)

GDF11: Growth differentiation factor 11; TME: Tumor microenvironment; OXPHOS: Oxidative phosphorylation; ROS: Reactive oxygen species; CD: Cluster of differentiation.

Table 2 Growth differentiation factor 11-induced secretome shift in M2-like macrophages

Cytokine/factor family	Mediator	Baseline M2 secretion	GDF11 treatment effect	Functional consequence on tumor cells
Pro-tumoral/angiogenic	IL-6	High	Significantly (decrease)	Reduced proliferation, survival, and metastasis
Pro-tumoral/angiogenic	ENA-78 (CXCL5)	Moderate/high	Significantly (decrease)	Reduced cell migration and invasiveness
Pro-tumoral/angiogenic	Angiogenin	Moderate/high	Significantly (decrease)	Inhibition of tumor vascularization
Pro-inflammatory/anti-tumoral	IL-1beta	Low	Significantly (increase)	Induction of anti-tumoral inflammatory signaling
Pro-inflammatory/anti-tumoral	TNF-α	Low	Significantly (increase)	Direct cytotoxic effect on tumor cells
Chemotactic/immune recruitment	MCP-1, MCP-2, MCP-3, regulated upon activation normal T cell expressed and secreted	Variable	Significantly (increase)	Recruitment of anti-tumoral immune cells (such as T-cells)

GDF11: Growth differentiation factor 11; MCP: Monocyte chemoattractant protein; IL: Interleukin; TNF: Tumor necrosis factor.

Table 3 Future therapeutic applications and research directions for growth differentiation factor 11 in oncology

Application focus	Suggested approach	Rationale	Research priority
Pan-cancer therapy	GDF11 agonists/mimetics	Directly drive TAM reprogramming and enhance anti-tumor immunity without systemic cytotoxicity in multiple TMEs	In vivo safety and efficacy in models of various solid tumors (including breast, lung, colorectal)
Combination therapy	GDF11 + immunotherapy	Combine GDF11-mediated M2-reversal with checkpoint blockade (PD-1/PD-L1) to overcome TAM-driven immune exclusion/suppression	Evaluate synergistic effects in clinically resistant or “cold” tumors
Metabolic disease	GDF11 for NASH/fibrosis	Reverse M2-like phenotype in chronic inflammation that predisposes tissues to malignancy (including liver fibrosis, HCC)	Efficacy in chronic inflammatory liver disease models (such as diet-induced NASH)
Molecular targeting	Metabolic checkpoint inhibition	Identify and target the specific metabolic enzymes (in cholesterol or OXPHOS pathways) regulated by GDF11 for targeted drug development	Detailed multi-omics analysis (metabolomics, transcriptomics) of GDF11-treated TAMs

NASH: Non-alcoholic steatohepatitis; GDF11: Growth differentiation factor 11; TAM: Tumor-associated macrophage; TME: Tumor microenvironment; OXPHOS: Oxidative phosphorylation; PD-1: Programmed cell death 1; PD-L1: Programmed cell death ligand 1; HCC: Hepatocellular carcinoma.