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

Lung adenocarcinoma, a predominant subtype of non-small cell lung cancer (NSCLC), is frequently driven by mutations in the KRAS oncogene. While KRAS mutations have long been linked to tumor proliferation and poor prognosis, their role in modulating the tumor immune microenvironment has remained elusive. The current study focuses on the molecular crosstalk between KRAS mutations and immune checkpoint regulation, particularly how PD-L1 expression is upregulated, facilitating tumor immune escape.

The immune checkpoint molecule PD-L1 serves as a primary shield for tumor cells, binding to PD-1 receptors on CD8+ cytotoxic T lymphocytes to inhibit their function. This interaction dampens the immune system’s ability to recognize and eliminate malignant cells. Although KRAS mutation was previously observed to elevate PD-L1 levels, the underlying signaling intermediates responsible for this regulation had not been fully elucidated until now.

Through meticulous analysis of lung adenocarcinoma tissue samples and cell lines harboring KRAS mutations, the researchers found a direct correlation between KRAS activity and the expression of ZNF24, a zinc finger transcription factor, and SLC7A5, an amino acid transporter. ZNF24 appears to act as a pivotal regulator that links KRAS signaling to the enhancement of PD-L1 expression via SLC7A5, effectively creating an immune-suppressive milieu.

Experimental data demonstrated that mutant KRAS upregulates ZNF24, which in turn increases the expression of SLC7A5. This transporter not only facilitates nutrient uptake critical to tumor growth but also mediates the elevation of PD-L1 on the tumor cell surface. Consequently, PD-L1’s interaction with PD-1 on CD8+ T cells leads to their inactivation, allowing the tumor cells to evade immune detection and destruction.

To validate these findings, the study utilized both in vitro coculture systems and in vivo murine models. CD8+ T cells exposed to KRAS mutant tumor cells exhibited markedly reduced cytotoxic activity, confirming that the ZNF24/SLC7A5/PD-L1 axis exerts a potent immunosuppressive effect. Importantly, the suppression of ZNF24 reversed PD-L1 overexpression and reinstated CD8+ T cell function, highlighting the axis as a promising therapeutic target.

In a pioneering effort, the researchers identified Daptomycin (DAPT), an antibiotic conventionally used to treat bacterial infections, as the first known inhibitor of ZNF24. Molecular binding assays revealed that DAPT interacts directly with ZNF24, effectively incapacitating its transcriptional regulatory function. This unprecedented finding repurposes an existing drug as a potential modulator of immune checkpoint pathways in cancer.

Combination therapy experiments further underscored the translational significance of these discoveries. Combining DAPT with anti-PD-L1 monoclonal antibodies synergistically enhanced CD8+ T cell-mediated tumor killing in KRAS mutant models, surpassing the efficacy of either agent alone. This synergy provides a compelling rationale for clinical trials exploring dual targeting of ZNF24 and PD-L1 in lung adenocarcinoma patients.

The implications of this research extend beyond lung adenocarcinoma, considering that KRAS mutations and PD-L1-mediated immune evasion are common hallmarks in various malignancies. Targeting the newly defined ZNF24/SLC7A5/PD-L1 axis may revolutionize immunotherapy, particularly for tumors notoriously resistant to current checkpoint inhibitors.

Furthermore, the study underscores the importance of dissecting the nuanced molecular networks orchestrated by oncogenic mutations. As cancer therapy evolves toward precision medicine, understanding how mutations like those in KRAS drive immune escape mechanisms will be paramount in designing effective combination regimens that restore antitumor immunity.

While PD-1/PD-L1 inhibitors have transformed the clinical landscape for many cancer patients, their success in KRAS mutant lung adenocarcinoma has been limited. The revelation of ZNF24 as a nodal point controlling PD-L1 expression offers a novel target to circumvent innate resistance, potentially expanding the benefit of immunotherapy to a broader patient population.

This comprehensive investigation also prompts deeper inquiry into the role of amino acid transporters such as SLC7A5 in tumor-immune interactions. Beyond nutrient provision, SLC7A5’s involvement in immune checkpoint regulation reflects the complex metabolic-immune axis exploited by cancer cells to survive hostile environments.

Looking ahead, clinical translation will require rigorous evaluation of DAPT and related compounds’ safety and efficacy in oncology settings. Nonetheless, repositioning existing drugs offers a pragmatic shortcut in drug development, potentially accelerating the availability of novel treatments for patients with limited options.

In sum, this landmark study delineates a previously unrecognized pathway by which KRAS mutations hijack immune checkpoint regulation, fostering immune escape through a cascade involving ZNF24 and SLC7A5 that culminates in PD-L1 upregulation. The identification of a pharmacological inhibitor that can disrupt this axis represents a transformative advance with far-reaching therapeutic implications.

Ongoing research will no doubt build upon this foundation, exploring combinatorial strategies that integrate metabolic modulation and immune checkpoint blockade. Ultimately, these insights bring us closer to overcoming one of the most resilient barriers in cancer treatment: the tumor’s capacity to silently thwart immune surveillance.

Subject of Research: KRAS mutation-induced immune escape mechanisms in lung adenocarcinoma via the ZNF24/SLC7A5/PD-L1 signaling axis.

Article Title: KRAS mutation promotes immune escape of lung adenocarcinoma via ZNF24/SLC7A5/PD-L1 axis.

Article References:
Li, L., Feng, Q., Jiang, Y. et al. KRAS mutation promotes immune escape of lung adenocarcinoma via ZNF24/SLC7A5/PD-L1 axis. BMC Cancer 25, 1417 (2025). https://doi.org/10.1186/s12885-025-14336-0

Image Credits: Scienmag.com

DOI: https://doi.org/10.1186/s12885-025-14336-0