Reversing Macrophage Metabolism May Improve Cancer Immunotherapy Outcomes
Key Insights
Tumor-associated macrophages undergo metabolic reprogramming in the tumor microenvironment that drives them toward a pro-tumor, immunosuppressive state across multiple cancer types.
A comprehensive review from Southern Medical University (search) systematically dissects how glucose, lipid, and amino acid metabolic pathways are hijacked in TAMs to promote tumor growth and immune evasion.
Therapeutic strategies targeting TAM metabolism—including enzyme inhibitors, repolarization agents, and phagocytosis-restoring antibodies—show promise for reprogramming macrophages back to tumor-fighting states.
Tumor-associated macrophages (TAMs)—among the most abundant immune cells in the tumor microenvironment—are typically co-opted to support tumor growth, metastasis, and therapeutic resistance rather than attacking cancer cells. A new review published in Cancer Biology & Medicine from researchers at the Medical Research Institute, Guangdong Provincial People's Hospital, Academy of Medical Sciences, Southern Medical University (search) in Guangzhou, China, systematically dissects how metabolic rewiring in TAMs drives immunosuppression across multiple cancer types and outlines a broad spectrum of therapeutic opportunities to reverse this process.
"TAMs are not passive bystanders but active metabolic partners that tumors corrupt to sustain their own growth," the authors stated. "What excites us is that this metabolic reprogramming is reversible. By understanding exactly how tumors hijack macrophage metabolism, we can design therapies that flip these cells back to their tumor-fighting state."
The Metabolic Battlefield of the Tumor Microenvironment
The tumor microenvironment presents a hostile metabolic landscape where dysfunctional blood vessels create nutrient and oxygen deprivation, while cancer cells flood the space with toxic byproducts like lactate and adenosine that suppress immune surveillance. Within this environment, TAMs undergo a metabolic transformation intrinsically linked to their shift toward a pro-tumor state.
The review unveils a sophisticated network of metabolic manipulation spanning glucose, lipid, and amino acid pathways. In glucose metabolism, tumor-derived lactate drives histone lactylation in TAMs—an epigenetic modification that silences retinoic acid receptor-γ expression and activates nuclear factor-kappa B, triggering interleukin-6 production that propels colorectal tumor growth. Additionally, the glycolytic enzyme pyruvate kinase M2 (search) directly binds hypoxia-inducible factor-1α at PD-L1 (search) promoter sites, boosting immune checkpoint expression.
Lipid and Amino Acid Pathways Under Siege
In lipid metabolism, the scavenger receptor CD36 (search) emerges as a pivotal player. Lipid-loaded vesicles absorbed through CD36 fuel fatty acid oxidation and promote M2-like polarization that suppresses CD8⁺ T cell activity. The nCDase-sphingosine-1-phosphate axis drives TREM2 (search)⁺ immunosuppressive macrophage accumulation in breast cancer (search), while tumor-secreted GRP78 enters macrophages and anchors to lipid droplets, stabilizing adipose triglyceride lipase to steer cells toward an anti-inflammatory state.
Amino acid pathways are equally exploited: glutamine powers tricarboxylic acid cycle anaplerosis and spermidine synthesis; tryptophan metabolites from gut microbiota activate aryl hydrocarbon receptor in TAMs; and arginase-1 (search) depletes arginine to generate polyamines that engage p53 signaling. The review further spotlights itaconate and succinate as pro-tumor TCA cycle intermediates that enforce immunosuppression via epigenetic remodeling.
Therapeutic Strategies and Emerging Challenges
Therapeutic approaches targeting TAMs are advancing rapidly. Strategies range from TAM depletion via colony-stimulating factor-1 receptor and C-C chemokine receptor type 2 inhibitors, to repolarization through CD40 agonists and TREM2 (search) antagonists, to metabolic targeting with small molecules against glutaminase, arginase-1 (search), and fatty acid-binding protein 5. The CD47 (search)-signal regulatory protein alpha and CD24-sialic acid-binding Ig-like lectin 10 "don't eat me" pathways also offer promising avenues to restore macrophage phagocytosis.
Yet significant obstacles remain. Metabolic compensation can drive resistance, off-target effects and toxicities pose safety concerns, and the ever-shifting tumor microenvironment complicates drug design. The authors stress that next-generation strategies—including chimeric antigen receptor macrophage therapies and rational combination regimens—will be essential to overcome these hurdles and unlock the full potential of TAM-directed immunotherapy.
The review, published with DOI 10.20892/j.issn.2095-3941.2025.0626, provides a comprehensive framework for understanding how metabolic reprogramming drives TAM function and highlights the urgent need to translate these mechanistic insights into viable clinical strategies.