Immunotherapy has revolutionized cancer treatment by empowering the immune system to recognize and destroy malignant cells. Despite its promise, this approach only benefits about 20% of patients, which poses a significant challenge for oncologists trying to predict who will respond favorably. A groundbreaking study from the Rutgers Cancer Institute, published recently in Cell Reports Medicine, sheds new light on overcoming this obstacle by identifying a novel biomarker and a synergistic therapeutic strategy that could dramatically boost immunotherapy’s efficacy.
The central focus of this research is PHGDH, a metabolic enzyme that plays a pivotal role in cancer cell biology. PHGDH catalyzes the first step in serine biosynthesis, a non-essential amino acid vital for rapid tumor growth. Many cancers, including roughly half of colorectal cancers and 40% of breast cancers, exhibit abnormally high levels of PHGDH, making it an attractive target for drug development. However, until now, the potential of PHGDH in cancer immunology remained unexplored.
Rutgers researchers, led by Professor Zhaohui Feng and assistant professor Juan Liu, unveiled a surprising noncanonical function of PHGDH that extends beyond its metabolic role. They discovered that PHGDH directly stimulates the production of PD-L1, a protein on tumor cells that inhibits immune attack by binding to PD-1 receptors on T-cells. PD-L1 blockade underpins the mechanism of several FDA-approved immunotherapy drugs, including checkpoint inhibitors, which aim to unleash the immune response against tumors.
Intriguingly, the team demonstrated that PHGDH’s promotion of PD-L1 expression operates independently of its enzymatic activity related to serine synthesis. By engineering mutated forms of PHGDH incapable of metabolic function, they confirmed that these inactive variants still elevated PD-L1 levels, revealing a dual role for PHGDH in tumor growth and immune evasion. This finding challenges the conventional understanding of metabolic enzymes as single-function entities.
Current experimental PHGDH inhibitors are designed to shut down the enzyme’s metabolic function, thereby starving tumors of serine. However, these drugs do not eliminate the PHGDH protein itself, leaving its immune-modulating activity intact. This distinction is critical because it means that such inhibitors may not fully counteract cancer’s ability to hide from the immune system despite reducing tumor fuel supply.
To address this complexity, Feng and his team hypothesized that combining PHGDH metabolic inhibitors with immunotherapy drugs targeting PD-L1 or PD-1 could have a powerful, synergistic effect. Testing this dual approach in mouse models, they observed a near threefold increase in survival compared to either treatment alone. Approximately 50% of mice receiving both drugs survived 60 days without signs of toxicity, whereas survival in single-treatment groups hovered around 20%, and untreated controls saw no long-term survivors.
These preclinical results suggest that attacking tumors on two fronts—metabolic deprivation and immune unmasking—can overcome resistance mechanisms that limit current immunotherapy efficacy. If translated into clinical practice, this approach holds promise for dramatically improving outcomes in cancers characterized by high PHGDH expression.
Beyond therapeutic innovation, the study identified PHGDH as a potent predictive biomarker for immunotherapy responsiveness. Analyzing existing clinical data, the researchers found that cancer patients with tumors expressing elevated PHGDH levels were significantly more sensitive to anti-PD-1 therapies. This biomarker could prove instrumental in personalizing treatment decisions, sparing patients unlikely to benefit from unnecessary side effects and costs associated with immunotherapy.
Feng emphasized this translational potential, explaining that quantifying PHGDH levels in tumors might soon guide oncologists in selecting patients most likely to respond to checkpoint inhibitors. Such biomarker-driven approaches advance the precision oncology paradigm, optimizing therapeutic efficacy on an individual basis.
The discovery integrates metabolic biology and immuno-oncology in a novel conceptual framework, highlighting how enzymes traditionally classified by their metabolic function can have multifaceted roles in cancer pathogenesis. It challenges researchers to re-evaluate the complexity of tumor biology and the interconnectedness of metabolic and immune pathways.
As PHGDH inhibitors proceed through preclinical development, regulatory approval will be essential before this combination strategy can be tested in human clinical trials. Meanwhile, ongoing biomarker validation studies aim to confirm the robustness of PHGDH expression as a predictive tool across larger and more diverse patient cohorts.
Funding from the National Institutes of Health, the New Jersey Commission on Cancer Research, the New Jersey Health Foundation, and Ludwig Research Support was critical to advancing this multidisciplinary investigation. This study exemplifies the collaborative synergy needed to translate bench discoveries into potential life-saving therapies.
This groundbreaking research opens new horizons not only for colorectal and breast cancers but also potentially for other malignancies where PHGDH plays a role. It underscores the urgency of exploring enzyme functions beyond metabolism and integrating these insights into innovative treatment paradigms that enhance immunotherapy’s reach.
As the oncology community awaits further clinical validation, patients and physicians alike can find hope in these advances. Understanding the dual roles of PHGDH may ultimately transform how cancers are treated, moving us closer to personalized, highly effective therapies that address both tumor growth and immune evasion.
Subject of Research: Animals
Article Title: Targeting the noncanonical function of metabolic enzyme PHGDH in driving PD-L1 expression and cancer immune evasion
News Publication Date: 28-Mar-2026
Web References: http://dx.doi.org/10.1016/j.xcrm.2026.102704
Keywords: Cancer immunotherapy, PHGDH, PD-L1, checkpoint inhibitors, metabolic enzyme, serine biosynthesis, immune evasion, biomarker, colorectal cancer, breast cancer, combination therapy
