Metabolic enzyme PHGDH played a surprising role in breast cancer immunity

Metabolic enzyme PHGDH played a surprising role in breast cancer immunity

Macrophages are immune cells with a split personality: some fight tumors while others help them grow. In breast cancer, most macrophages fall into the latter camp - M2-like, leading to tumor progression and dampening immune responses. This shift is influenced by the tumor microenvironment, where limited nutrients and oxygen force immune cells to a metabolic drag. One pathway under scrutiny is serine biosynthesis, which is regulated by the enzyme PHGDH. Although its role in metabolism is well documented, PHGDH's macrophage behavior has remained unclear. Because of these challenges, it is important to investigate how metabolic signals shape the identity and function of immune cells in tumors.

A collaborative team from Sun Yat-Sen University and Zhejiang Cancer Hospital published a new study (doi: 10.20892/j.issn.2095-3941.2024.0398) inCancer Biology & Medicineand shows that the metabolic enzyme PHGDH plays a surprising role in breast cancer immunity. Instead of being limited to metabolic pathways, PHGDH translocates into the nucleus of macrophages, where it suppresses the key to glutamine metabolism. In this way, it steers immune cells away from an immunosuppressive state towards tumor-fighting behavior. The results reveal a previously unknown function of PHGDH and suggest new strategies for remodeling the tumor microenvironment.

The researchers began by profiling immune cell behavior and metabolism in breast cancer tissue and model systems. They found that PHGDH expression is reduced in tumor-associated macrophages and that these cells have reduced activity in serine biosynthesis and glycolysis - two pathways essential for immune activation. Notably, PHGDH was translocated to the nucleus during macrophage polarization. There it is tied to the organizers ofGlud1AndGLS2Blocking their transcription by partnering with STAT3, a well-known transcription factor. This suppression in glutamine metabolism, an important fuel source for immunosuppressive m2-type macrophages.

To test the function, the team manipulated PHGDH levels in both human and mouse macrophages. Inhibited PHGDH-amplified markers of M2-like behavior and immune checkpoint molecules such as PD-L1, while restoring PHGDH tip cells toward M1-like antitumor states. Mouse models showed that macrophages engineered to overexpress PHGDH slowed tumor growth and reduced cell proliferation. Further experiments showed that glutamine supplementation or STAT3 inhibition could counteract PhgdH loss and strengthen the regulatory loop between metabolism, transcription and immune polarization.

This study challenges our understanding of PHGDH. We have long known PHGDH as a metabolic enzyme, but finding it to function in the nucleus and directly regulate immune behavior was unexpected. It acts like a molecular switch – by suppressing important genes, it redirects macrophages from supporting tumors to fighting them. This is a paradigm shift in how we think about metabolism and immunity. “

Dr. Zhenkun NA, senior author of the study

The discovery that nuclear PHGDH reprograms macrophages offers a compelling new therapeutic strategy. By targeting PHGDH or its downstream partners, the immune landscape of tumors can be rewired—to turn so-called “bad” macrophages into cancer treatment allies. These results could improve the effectiveness of immunotherapies, particularly in cancers resistant to checkpoint blockade. Furthermore, PHGDH levels could serve as biomarkers for stratifying patients or monitoring treatment responses. As cancer research increasingly overlaps with immunometabolism, PHGDH stands out as a key player in the next generation of precision oncology.

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