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

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.