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Targeting macrophage metabolism to enhance tumor immunotherapy

Cellular & Molecular Immunology (2024)Cite this article

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Tumor-associated macrophages (TAMs) are important components of the tumor microenvironment (TME) and are characterized by plasticity and heterogeneity. This heterogeneity reflects the ability of macrophages to respond to environmental stimuli, leading to their differentiation from proinflammatory (M1-like) to anti-inflammatory (M2-like) phenotypes [1]. Specific subsets of TAMs mediate different processes, such as orchestrating angiogenesis, extracellular matrix remodeling, cancer cell proliferation, metastasis, and immunosuppression, by providing malignant cells with trophic and nutrient support, which is mostly related to poorer clinical outcomes [2, 3]. Moreover, TAMs mediate tumor phagocytosis and promote antitumor immunity, leading to better clinical outcomes. Thus, how to regulate TAMs to reverse their transition from the M2-like phenotype to the M1-like phenotype is an urgent scientific issue.

Serine metabolism is known to regulate immune cell functions, but how it specifically regulates macrophage polarization remains largely unclear [4]. In a recent study, Cai et al. [5] reported that phosphoglycerate dehydrogenase (PHGDH)-mediated serine biosynthesis promoted α-ketoglutarate (α-KG) production, activated mammalian target of rapamycin C1 (mTORC1) signaling and contributed to the maintenance of an M2-like macrophage phenotype in the TME. Cai et al. [5] used genetic approaches to ablate the Phgdh gene in macrophages and discovered that PHGDH was required for the immunosuppressive activation of the Th2 cytokine interleukin (IL)-4. Deletion of Phgdh augmented the development of the LPS-induced inflammatory phenotype. In a syngeneic mouse model of mesothelioma, PHGDH expression was strongly increased in TAMs, and conditional deletion of Phgdh suppressed TAM infiltration and delayed tumor growth. Additionally, the PHGDH-mediated serine synthesis pathway plays a crucial role in regulating the conversion of glutamate to α-KG, which is necessary for mTORC signaling activation and sustains immunosuppressive M2 activation and TAM expansion. These findings provide a strong basis for further exploration of PHGDH as a potential target to counteract TAM-mediated immunosuppression and inhibit tumor progression.

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Funding

This study was funded by the National Natural Science Foundation of China (NSFC) (82071771, 82271807 to PL), the Hubei Province Science Fund for Distinguished Young Scholars (2022CFA057 to PL), and the Nonprofit Central Research Institute Fund of Chinese (2023-PT320-07).

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Authors and Affiliations

  1. Institute of Organ Transplantation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Jing Liu, Zhibo Ma & Peixiang Lan

  2. Key Laboratory of Organ Transplantation, Ministry of Education, NHC Key Laboratory of Organ Transplantation, Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, People’s Republic of China

    Jing Liu, Zhibo Ma & Peixiang Lan

  3. Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of China

    Wenlong Jia

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  1. Jing Liu
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Correspondence to Peixiang Lan.

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Liu, J., Ma, Z., Jia, W. et al. Targeting macrophage metabolism to enhance tumor immunotherapy. Cell Mol Immunol (2024). https://doi.org/10.1038/s41423-024-01149-7

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