Metabolic enzyme PHGDH found to play 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—dubbed M2-like—fueling tumor progression and dampening immune responses. This shift is influenced by the tumor microenvironment, where limited nutrients and oxygen force immune cells into a metabolic tug-of-war. One pathway under scrutiny is serine biosynthesis, regulated by the enzyme PHGDH. Though its role in metabolism is well documented, how PHGDH influences macrophage behavior has remained unclear. Due to these challenges, it is necessary to explore how metabolic signals shape immune cell identity and function 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) in Cancer Biology & Medicine, revealing that the metabolic enzyme PHGDH plays a surprising role in breast cancer immunity. Instead of staying confined to metabolic pathways, PHGDH translocates into the nucleus of macrophages, where it suppresses genes key to glutamine metabolism. By doing so, it steers immune cells away from an immunosuppressive state and toward tumor-fighting behavior. The findings spotlight a previously unknown function of PHGDH and point to 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 diminished in tumor-associated macrophages, and that these cells show reduced activity in serine biosynthesis and glycolysis—two pathways essential for immune activation. Remarkably, PHGDH was observed relocating to the nucleus during macrophage polarization. There, it bound to the promoters of GLUD1 and GLS2, blocking their transcription by partnering with STAT3, a known transcription factor. This suppression reined in glutamine metabolism, a key fuel source for M2-type immunosuppressive macrophages.

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

This study turns our understanding of PHGDH on its head. We've long known PHGDH as a metabolic enzyme, but to find it functioning inside the nucleus, directly regulating immune behavior, was unexpected. It acts like a molecular switch—by repressing key genes, it redirects macrophages from supporting tumors to fighting them. That's 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, it may be possible to rewire the immune landscape of tumors—turning so-called "bad" macrophages into allies of cancer treatment. These findings could enhance the effectiveness of immunotherapies, particularly in cancers resistant to checkpoint blockade. Moreover, PHGDH levels could serve as a biomarker to stratify patients or monitor treatment responses. As cancer research increasingly intersects with immunometabolism, PHGDH stands out as a key player in the next generation of precision oncology.