Research Reveals Potential Target for Enhancing Immunotherapy in Cancer Treatment

A recent study published in Cellular & Molecular Immunology by a scientific team from the University of Vienna and the MedUni Vienna has uncovered a significant breakthrough in cancer treatment. The research reveals that the enzyme phosphoglycerate dehydrogenase (PHGDH) acts as a metabolic checkpoint in tumor-associated macrophages (TAMs), affecting tumor growth. This discovery opens new possibilities for targeting PHGDH to modulate the cancer-fighting immune system, potentially improving the effectiveness of clinical immunotherapies. 

The immune system plays a crucial role in combating cancer cells that emerge due to mutations. Among the key players in this process are macrophages, a type of immune cell. Tumor-associated macrophages (TAMs) are particularly abundant within the tumor microenvironment. These TAMs originate from immune cells present in the bloodstream, which infiltrate the tumor and differentiate in response to various signals, such as cytokines and growth factors. 

In many solid tumors, TAMs are paradoxically considered to be tumor-promoting, or “protumorigenic.” They facilitate tumor growth and metastasis by suppressing immune responses, promoting vascularization within the tumor, and increasing resistance to drug therapies. Consequently, elevated levels of TAMs often correlate with a poor prognosis for cancer patients. Previous attempts to manipulate TAMs therapeutically have had limited success, highlighting the urgent need for innovative approaches. 

The study, led by systems biologist and biochemist Wolfram Weckwerth from the University of Vienna, utilized innovative methods of artificial intelligence (AI) and machine learning combined with molecular analyses to uncover a metabolic checkpoint in macrophage polarization. This approach, termed the “COVRECON strategy,” integrates techniques from biochemistry, genetics, and metabolomics with principles of mathematical control theory to gain insights into cellular metabolic processes. 

The researchers identified PHGDH as a key regulator of macrophage activity, controlled by various signaling pathways. Given that TAMs resemble a subtype of normal macrophages known as M2 macrophages, which exhibit immunosuppressive and protumorigenic properties, the team investigated the impact of PHGDH on TAM functionality and tumor growth. 

Lead author Zhengnan Cai from the University of Vienna explains, “In our study, we used genetic approaches to explore the role of PHGDH in macrophages. We found that PHGDH is essential for activating immunosuppressive M2 macrophages, while its suppression promotes the development of antitumorigenic M1 macrophages, ultimately leading to reduced tumor growth.” 

The research team also uncovered the critical role of the PHGDH-mediated serine metabolic pathway in regulating key cellular processes associated with TAMs, including the mTORC1 signaling pathway, which controls cell growth, differentiation, and metabolism. Additionally, PHGDH influences the expression of the immune checkpoint protein PD-L1, further highlighting its significance in modulating the tumor microenvironment. 

Weckwerth summarizes the findings, stating, “Our study provides fundamental insights into the interplay between immune regulation and cancer development. By targeting PHGDH and modulating TAMs, we may develop strategies to combat tumors effectively. However, further investigations are necessary to fully understand and harness the potential of this approach.” 

This groundbreaking research represents a significant step forward in cancer treatment. By elucidating the role of PHGDH in TAM function and tumor growth, the study offers new avenues for therapeutic intervention. Targeting PHGDH could potentially enhance the efficacy of existing immunotherapies and improve patient outcomes in various cancer types. 

Moreover, the integration of AI and machine learning techniques in biological research demonstrates the power of interdisciplinary approaches in unraveling complex biological processes. The study underscores the importance of collaboration between disciplines to address pressing challenges in cancer biology and therapeutics. 

Looking ahead, continued research into the mechanisms underlying TAM regulation and the development of targeted therapies will be essential. By leveraging insights from this study, researchers aim to refine cancer treatment strategies and improve patient survival rates. 

In conclusion, the study by the University of Vienna and the MedUni Vienna offers promising prospects for cancer treatment by uncovering the pivotal role of PHGDH in TAM-mediated tumor growth. This research represents a significant advancement in our understanding of cancer biology and opens new avenues for therapeutic innovation. 

Journal Infromation  

Dimitrios Bitounis et al, Strategies to reduce the risks of mRNA drug and vaccine toxicity, Nature Reviews Drug Discovery (2024). DOI: 10.1038/s41573-023-00859-3.