Recently, scientists from the University of Vienna and other institutions discovered that phosphoglycerate dehydrogenase (PHGDH) may play a role as a metabolic checkpoint in tumor-associated macrophages (TAMs), thereby influencing tumor growth. Targeting PHGDH to modulate the immune system against cancer may be a new beginning for cancer therapies and could improve the efficacy of clinical immunotherapy.

Among the many molecular players within TAM, PHGDH has received attention for its unique role in regulating metabolic pathways critical for tumor survival and proliferation. Creative Biolabs delves deeper into this intriguing topic, exploring specific enzyme checkpoints in TAM and their impact in cancer biology. With a team of experienced scientists and facilities designed to meet every challenging requirement in macrophage therapeutics development, we can provide fast, reliable support at any stage of macrophage therapeutics development.

PHGDH and TAMs

PHGDH plays an important role in the synthesis of macromolecules, neutralization of oxidative stress, and regulation of methylation reactions in cancer cells, lymphocytes, and endothelial cells; however, researchers are not aware of the key role that PHGDH plays in TAMs.

Fig. 1 The domain structures of the three types of PHGDH.¹

The body's immune system constantly fights against cancer cells generated by mutations, a process controlled by different types of macrophages, and one of the most abundant immune cells in the tumor microenvironment is the TAM, which is derived from tissue-resident immune cells circulating in the bloodstream that infiltrate the tumor and continuously differentiate in response to a variety of cytokines and growth factors.

In most solid tumors, TAM is paradoxically thought to promote tumorigenesis by suppressing the body's immune response to promote tumor growth and metastasis, as well as to promote vascularization of the tumor and increase its resistance to therapies. As many patients have very limited responses to these therapies, previous attempts to influence TAM have also proved to be less than optimal, which perhaps emphasizes the urgency of finding new active ingredients and strategies. PHGDH may be a promising breakthrough.

Metabolic Checkpoint for TAM - PHGDH

Some researchers have combined innovative methods of machine learning and artificial intelligence with molecular analysis to discover a new metabolic checkpoint - PHGDH - in the polarization of macrophages.

The researchers found that the activity of the enzyme PHGDH is controlled by different signaling pathways and affects the cellular activity of macrophages, and since the properties of TAM on immunosuppressive and pro-tumorigenic immune cells are similar to a subtype of normal macrophage (called M2-type), the researchers were ready to start investigating - the function of PHGDH and its effect on tumor growth. It is worth noting that we are able to offer a wide range of products for macrophage therapeutics related signaling pathway research.

The researchers investigated the function of PHGDH in macrophages through a joint study using genetic methods. It was found that PHGDH is important for the activation of immunosuppressive M2 macrophage subtypes, and on the other hand, suppression of the PHGDH gene may promote the development of tumor-resistant (M1) macrophages and reduce tumor growth.

Researchers suggest that the PHGDH-mediated serine metabolic pathway may play a key role in processes related to

• The regulation of the mTORC1 signaling pathway (which plays a key role in the regulation of cell growth, cellular differentiation, and cellular metabolism).
• The activation of immunosuppressive M2 macrophages.
• The expansion of tumor-associated macrophages.
• The regulation of the immune checkpoint PD-L1.

Key Mechanisms Through Which PHGDH Influences TAM-mediated Tumor Progression

Recent studies have shed light on the subtle role of PHGDH in TAM biology, revealing specific enzymatic checkpoints that shape its phenotype and function in TME. Here, we describe the key mechanisms by which PHGDH influences TAM-mediated tumor progression.

• Regulation of macrophage polarization
  By promoting serine-dependent metabolic pathways, PHGDH maintains the metabolic requirements of M2-like TAM, thereby promoting its anti-inflammatory phenotype. Conversely, inhibition of PHGDH activity leads to metabolic stress and reprogramming of TAM to a pro-inflammatory M1-like phenotype, ultimately enhancing anti-tumor immunity and tumor suppression.
• Regulation of immunosuppressive functions
  PHGDH-mediated serine biosynthesis promotes the production of downstream metabolites such as glycine and one-carbon units, which are essential for the maintenance of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC). Thus, PHGDH inhibition attenuates the immunosuppressive environment within the TME, releasing an effective anti-tumor immune response and enhancing the efficacy of immunotherapy.
• Promote tumor cell survival and proliferation
  Through the secretion of serine and other metabolites, TAM provides essential nutrients and metabolic precursors to promote the growth and survival of neighboring cancer cells. Notably, PHGDH inhibition disrupts this metabolic crosstalk, impeding tumor cell proliferation and sensitizing malignant cells to cytotoxic therapies.

Given its multifaceted role in TAM biology and tumor progression, PHGDH emerges as an attractive therapeutic target for cancer intervention. Strategies aimed at selectively inhibiting PHGDH activity in TAM are expected to disrupt the metabolic symbiosis between cancer cells and TME, thereby unleashing an effective anti-tumor immune response and enhancing the efficacy of existing therapeutic modalities.

Creative Biolabs is dedicated to exploring the frontiers of macrophage biology and advancing innovative solutions for cancer treatment. Through our collaborative efforts and cutting-edge research programs, we strive to pave the way for more effective anti-cancer strategies.

References

1. Zhao, Jia-Ying, et al. "A retrospective overview of PHGDH and its inhibitors for regulating cancer metabolism." European journal of medicinal chemistry 217 (2021): 113379.
2. Cai, Zhengnan, et al. "Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling." Cellular & Molecular Immunology (2024): 1-18.