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

Abstract

This editorial comments on recent research by Escobedo-Calvario et al. 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.

Key Words: Growth differentiation factor 11; Macrophages; Immunometabolism; Macrophage polarization; Cancer; Tumor microenvironment; Hepatocellular carcinoma

Core Tip: Growth differentiation factor 11 (GDF11) is a potent immunometabolic modulator that can reprogram pro-tumoral M2-like macrophages primarily studied in hepatocellular carcinoma. GDF11 reverses their dysfunctional metabolic state by activating Smad2/3 signaling, restoring mitochondrial oxidative phosphorylation (as indicated by increased oxygen consumption rate), and reducing immunosuppressive cellular cholesterol. This critical metabolic shift induces the production of anti-tumoral cytokines and reactive oxygen species, neutralizing tumor cell proliferation and migration. GDF11 could be a promising, mechanism-based strategy to flip the immune-suppressive microenvironment toward tumor destruction.

INTRODUCTION

The progression of most solid tumors is characterized by a highly permissive tumor microenvironment (TME)[1]. A crucial and conserved pathological feature across these diverse malignancies is the abundance of tumor-associated macrophages (TAMs) that are polarized to M2-like phenotype[2,3]. Circulating monocytes infiltrate into tissue and form M2 macrophages. Their beneficial and physiological role lies in wound healing, tissue repair, and the resolution of inflammation[4]. They also function in minimizing damage during autoimmune disease flares[5]. However, when these M2-like macrophages infiltrate the TME, they are corrupted by TME cues and become metabolic opportunists, possessing a distinct, dysfunctional immunometabolic profile characterized by low oxidative phosphorylation (OXPHOS), a reliance on aerobic glycolysis, and high lipid storage[6]. This specific metabolic change is mainly linked to their primary functions which are promoting tumor growth, angiogenesis, tissue remodeling, and broad immunosuppression[7]. The critical balance between M2’s regenerative function and its pro-tumoral activity is lost in cancer. Effectively reversing this M2-like phenotype is essential for successful therapeutic intervention in a wide range of cancers, yet traditional approaches often fail to address the underlying metabolic programming that sustains the M2 identity[8].

The recent work by Escobedo-Calvario et al[9], which is published in World Journal of Gastroenterology offers a paradigm shift in addressing this pan-cancer challenge[9]. They introduced growth differentiation factor 11 (GDF11), a member of the transforming growth factor (TGF)-β superfamily, as a potent immunometabolic regulator capable of directly reprogramming M2-like macrophages in a manner that opposes tumor progression, demonstrating this effect in the hepatocellular carcinoma (HCC) context.

GDF11 REGULATES MACROPHAGE IMMUNOMETABOLIC REPROGRAMMING

The data presented by Escobedo-Calvario et al[9] show that GDF11 treatment induces a profound switch from the pro-tumoral M2-like state. This reprogramming begins at the signaling level, where GDF11 utilizes the canonical Smad2/3 signaling pathway often exploited for its anti-proliferative effects in other cell types, to transmit its immunomodulatory signal[10]. In line with these findings, other research has consistently confirmed that GDF11 activates the Smad2/3 cascade across various cell types, including cardiomyocytes and pre-adipocytes, often resulting in anti-hypertrophic or anti-differentiation effects[11,12]. Beyond this study, other reports have previously demonstrated that GDF11 exerts anti-tumoral effects in cancer cells by targeting lipid and bioenergetic metabolism, which aligns precisely with the metabolic observations made in the M2-like macrophages here[13]. GDF11 treatment causes a dramatic loss of the M2 characteristic surface marker, cluster of differentiation (CD) 206 (CD206, also known as mannose receptor), indicating a rapid and decisive de-polarization away from the pro-tumoral phenotype observed across previous studies[14]. The loss of M2 identity is accompanied by a functional shift toward an anti-tumoral state[15], as evidenced by the corresponding increase in M1-associated functional markers within the secretome, such as interleukin (IL)-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α). Although a rise in canonical M1 surface markers such as CD80 or CD86 was not reported, the change in cytokine output confirms a re-education that results in anti-cancer function[16].

M2-like macrophages are metabolically suppressed[7]. As demonstrated in Figure 1, GDF11 reverses this, significantly increasing the oxygen consumption rate, which serves as a proxy for enhanced mitochondrial respiratory function (OXPHOS). This shift from dysfunctional glycolysis toward an energetic OXPHOS-driven state is characteristic of a re-educated, functionally robust macrophage[17]. Concurrently, the study highlights a crucial decrease in total cellular cholesterol content, addressing the excessive lipid accumulation often necessary for M2 maintenance in the TME[18]. Furthermore, this metabolic re-education involves the suppression of basal glycolytic flux, reflected by a decrease in the extracellular acidification rate, and a functional enhancement of β-oxidation to process and clear accumulated lipids, leading to a profound transformation of the macrophage’s bioenergetic profile[19].

Figure 1 Growth differentiation factor 11-mediated immunometabolic reprogramming drives macrophage re-education and suppresses tumor aggressiveness. This figure is a mechanistic diagram showing how growth differentiation factor 11 (GDF11) treatment flips pro-tumoral macrophages into an anti-tumoral state, based on findings primarily in the hepatocellular carcinoma context. The baseline (left) shows an M2-like tumor-associated macrophage (pro-tumoral) characterized by small, dysfunctional mitochondria (low oxygen consumption rate), high cholesterol (lipid droplets), and high cluster of differentiation (CD) 206. It secretes pro-tumoral factors [interleukin (IL)-6, angiogenin] that promote cancer cell proliferation and migration. GDF11 treatment (center) leads to the GDF11-re-educated macrophage (anti-tumoral) on the right. Signaling through Smad2/3 triggers immunometabolic reprogramming, resulting in large, functional mitochondria (high oxygen consumption rate), reduced cholesterol, loss of CD206, and high reactive oxygen species production. This re-educated macrophage secretes anti-tumoral factors (tumor necrosis factor-alpha, IL-1beta), which effectively inhibit cancer cell proliferation and migration. TAM: Tumor-associated macrophage; CD: Cluster of differentiation; GDF11: Growth differentiation factor 11; OCR: Oxygen consumption rate; ROS: Reactive oxygen species; IL: Interleukin; TNF: Tumor necrosis factor.

The induced increase in reactive oxygen species (ROS) production is compelling. A controlled surge in ROS is a hallmark of classically activated (M1) or anti-tumoral macrophages, essential for their microbicidal activity and inflammatory signaling[20]. GDF11 drives this redox change, functionally arming the macrophage with anti-tumoral potential relevant in combating all cancers reliant on M2 support[21]. These combined effects are summarized in Table 1 and demonstrate GDF11’s potential to fundamentally dismantle the M2-like macrophage’s pro-tumoral identity by attacking its metabolic core (Figure 1).

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.

THE SECRETOME SHIFT AND FUNCTIONAL NEUTRALIZATION OF TUMOR CELLS

The true clinical relevance of this reprogramming is observed in the resulting secretome shift. The conditioned media from GDF11-treated macrophages was rendered incapable of promoting general tumor cell proliferation and migration (specifically HCC cells in the original study)[9]. This neutralization is due to a profound change in paracrine factors, detailed in Table 2.

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.

However, it is important to acknowledge the context-dependent nature of GDF11. While the TME findings are anti-tumoral, some studies in non-oncological contexts, such as myocardial infarction, demonstrate that GDF11 generally promotes the M2-like phenotype [associated with repair and increased IL-10 and vascular endothelial growth factor (VEGF)] by targeting the TGF-βR1/Smad2 pathway[22]. The metabolic shift induced by GDF11 within the TME, however, appears to override the typically pro-repair secretome, instead yielding a hostile, anti-cancer secretome dominated by inflammatory mediators and decreased angiogenic factors, offering a crucial distinction in its tumor-specific immunomodulation[23].

GDF11 significantly decreased the secretion of key pro-tumoral and angiogenic factors [IL-6, ENA-78 (CXCL5), angiogenin, and VEGF] which are typically leveraged by M2-like macrophages to support tumor survival and metastasis in various malignancies[24]. Simultaneously, GDF11 induced an increase in pro-inflammatory/anti-tumoral mediators (IL-1β, TNF-α) and a panel of chemokines [monocyte chemoattractant protein (MCP)-1, MCP-2, MCP-3, CCL2, and regulated upon activation normal T cell expressed and secreted]. This distinct secretome profile suggests GDF11 is not simply polarizing the cells to a classical M1 state, but rather to a re-educated, pro-inflammatory, and anti-tumoral hybrid phenotype that is highly hostile to surrounding tumor cells regardless of origin[9]. While some studies in non-oncological contexts, such as myocardial infarction, demonstrate that GDF11 generally promotes the M2-phenotype (associated with repair and increased IL-10 and VEGF) by targeting the TGF-βR1/Smad2 pathway[25], the findings here are uniquely positioned within the TME. The metabolic shift induced by GDF11 appears to override the typically pro-repair secretome, instead yielding a hostile, anti-cancer secretome dominated by inflammatory mediators and decreased angiogenic factors, offering a crucial distinction in its tumor-specific immunomodulation.

FUTURE DIRECTIONS AND THERAPEUTIC POTENTIAL IN ONCOLOGY

The identification of GDF11 as a regulator of macrophage immunometabolism opens several critical avenues for future research and clinical application for a subset of malignancies, where TAMs are implicated. This translational potential is detailed further in Table 3. The immediate challenges, as is often the case in moving from in vitro to clinical application, lie in confirming the systemic efficacy and safety of GDF11 administration or GDF11-mimicking compounds in in vivo models of multiple aggressive cancers (such as pancreatic, ovarian, lung). Preliminary evidence from HCC models indicates that GDF11 can reprogram M2-like TAMs toward an anti-tumoral phenotype and exert direct effects on tumor cell metabolism in specific experimental contexts. However, the broader assertion that GDF11 provides a consistent dual-axis therapeutic strategy across diverse cancer types requires validation in multiple preclinical models before clinical translation can be considered[17]. Accordingly, future studies should focus on in vivo models of multiple aggressive cancers (such as pancreatic, ovarian, and lung) to evaluate the systemic efficacy, safety, and context-dependence of GDF11 administration or GDF11-mimicking compounds. The molecular mechanisms underpinning the specific metabolic changes require finer resolution. Future work should investigate whether GDF11 directly regulates key metabolic checkpoints, such as PFKFB3 (glycolysis regulation) or adenosine 5’-monophosphate-activated protein kinase/peroxisome proliferators-activated receptor-γ pathways (lipid metabolism), to fully map the immunometabolic cascade[26].

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.

The applicability of GDF11 extends beyond oncology. Since M2-like macrophage dysfunction contributes to chronic inflammatory disorders such as atherosclerosis, non-alcoholic steatohepatitis, and various fibrotic diseases, GDF11 provides a promising therapeutic template for treating the fundamental immune imbalance underlying these conditions[27].

Escobedo-Calvario et al[9] have successfully moved GDF11 from a circulating factor associated with anti-aging into a decisive player in the TME’s immunometabolic landscape. Leveraging GDF11’s unique ability to correct the energetic and redox balance of M2-like macrophages represents a powerful and necessary step towards designing more effective, mechanism-based therapies against HCC, and indeed, a wide range of cancers and other chronic inflammatory diseases.

CONCLUSION

In conclusion, the work by Escobedo-Calvario et al[9] establishes GDF11 as an unappreciated yet powerful immunometabolic rheostat in the TME. By activating the Smad2/3 pathway, GDF11 exerts a profound and functionally decisive shift in M2-like macrophages. This shift is characterized by the restoration of mitochondrial OXPHOS, the clearance of accumulated cellular cholesterol, and a resulting transition from a pro-tumoral, immune-suppressive phenotype to a hostile, anti-cancer secretome. Leveraging GDF11’s ability to correct the energetic and redox imbalance of M2-like macrophages offers a necessary and novel approach to cancer therapy. This strategy targets the metabolic roots of immune evasion, providing a pathway to simultaneously neutralize tumor-supporting immune cells and impede cancer progression across a wide range of malignancies. GDF11, therefore, moves beyond its association with anti-aging into a decisive role as a mechanism-based therapeutic candidate for reversing tumor-driven immunometabolic dysfunction.

ACKNOWLEDGEMENTS

We would like to thank Mrs. Rahmati M for her kind help in preparing the figure.