Tumor-associated macrophages (TAMs) are among the most abundant immune cells in the tumor microenvironment.However,instead of attacking cancer cells, they are typically co-opted to support tumor growth, metastasis, and therapeutic resistance. The tumor microenvironment is a metabolic battlefield 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 hostile environment, TAMs undergo a metabolic transformation that is intrinsically linked to their shift toward a pro-tumor state. Given these challenges, there is an urgent need to better understand the precise molecular mechanisms by which metabolic reprogramming drives TAM function, and to translate these insights into viable therapeutic strategies.
The review, published (DOI: 10.20892/j.issn.2095-3941.2025.0626) in Cancer Biology & Medicine, comes from researchers at the Medical Research Institute, Guangdong Provincial People's Hospital, Academy of Medical Sciences, Southern Medical University in Guangzhou, China. The work systematically dissects how metabolic rewiring in TAMs drives immunosuppression across multiple cancer types, and outlines a broad spectrum of therapeutic opportunities, ranging from metabolic enzyme inhibitors that reprogram TAM function, to immune checkpoint blockers that restore macrophage phagocytosis, to combination regimens that overcome resistance.
The review unveils a sophisticated network of metabolic manipulation. 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. The glycolytic enzyme pyruvate kinase M2 directly binds hypoxia-inducible factor-1α at programmed death-ligand 1 (PD-L1) promoter sites, boosting immune checkpoint expression.
In lipid metabolism, the scavenger receptor CD36 emerges as a pivotal player. Lipid-loaded vesicles are absorbed through CD36, fueling fatty acid oxidation and promoting M2-like polarization that suppresses CD8⁺ T cell activity. The nCDase-sphingosine-1-phosphate axis drives TREM2⁺ immunosuppressive macrophage accumulation in breast cancer, 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 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.
"TAMs are not passive bystanders but active metabolic partners that tumors corrupt to sustain their own growth," the authors said. "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 challenge now is to translate these mechanistic insights into treatments that can reach the clinic and benefit patients."
Therapeutic strategies are advancing rapidly. Approaches 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 antagonists, to metabolic targeting with small molecules against glutaminase, arginase-1, and fatty acid-binding protein 5. The CD47-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 effectsandtoxicities, 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.
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References
DOI
10.20892/j.issn.2095-3941.2025.0626
Original Source URL
https://doi.org/10.20892/j.issn.2095-3941.2025.0626
Funding information
This work was supported by grants from the National Natural Science Foundation of China (Grant Nos. 82341013, 82130087, and 92357301).
About Cancer Biology & Medicine
Cancer Biology & Medicine (CBM) is a peer-reviewed open-access journal sponsored by China Anti-cancer Association (CACA) and Tianjin Medical University Cancer Institute & Hospital. The journal monthly provides innovative and significant information on biological basis of cancer, cancer microenvironment, translational cancer research, and all aspects of clinical cancer research. The journal also publishes significant perspectives on indigenous cancer types in China. The journal is indexed in SCOPUS, MEDLINE and SCI (IF 12.4), with all full texts freely visible to clinicians and researchers all over the world.