Edited by:
Dr. Peter Bunyard, PhD, Sitryx Therapeutics, United Kingdom
Dr. pharm. Marina Makrecka-Kuka, PhD, Sitryx Therapeutics, United Kingdom
Submission Status: Open | Submission Deadline: 15 April 2025
Since the 1950’s drugs that target key enzymes in metabolic pathways have been used to treat auto-immune conditions such as rheumatoid arthritis and Inflammatory Bowel Disease. Examples include methotrexate and 5-fluorouracil that primarily inhibit dihydrofolate reductase and thymidylate synthase respectively. These enzymes that play important roles in the 1-carbon metabolism pathway producing purines and pyrimidines for RNA and DNA synthesis required for cell growth and proliferation. Despite the success of these compounds significant issues remain, most notably challenging side-effect profiles caused by the fundamental role that these enzymes play in numerous biological processes beyond those driving disease; these side effects limit the tolerability and effectiveness of such therapies.
Advances in molecular biology techniques such as CRISPR and knockout mice have provided new insights over the role that various enzymes play in metabolic pathways and have demonstrated that immune cells can utilize various metabolic pathways differently from surrounding homeostatic processes allowing more targeted therapy. Recent work by Jefff Rathmell et al., demonstrated that Th1 and Th17 helper T-ells are more dependent on the 1-carbon metabolism enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) than the majority of cells in the body: expression is also strongly upregulated upon activation and proliferation. Selective inhibition of MTHFD2 therefore holds the promise of being able to more specifically reduce inflammation without the debilitating side effects of methotrexate.
Beyond autoimmunity, immunometabolism may also play important roles in oncology and diet driven inflammation. For example, obeticholic acid has demonstrated efficacy in animal models of non-alcoholic steatohepatitis through modulating the farnesoid X receptor and subsequently inhibiting hepatic gluconeogenesis and fatty acid synthesis. The tumor micro-environment has also been shown to be devoid of numerous metabolites required to maintain the function of tumor killing CD8+ T-cells and also contains metabolites that can enhance T-reg immune tolerance.
Given the fundamental role for metabolism in the immune system, the knowledge that existing therapies modulate immune metabolism and that numerous targetable enzymes, transporters and receptors exist - immunometabolism remains at the forefront of medicinal research and drug discovery. However new insights that demonstrate the role of immunometabolism in basic and clinical research and highlight the importance of key molecules in metabolism pathways are urgently required. In this regard, we welcome original research articles (including preclinical and clinical trials, epidemiological studies, and case studies), comprehensive reviews, meta-analysis reports, and commentaries.
Potential topics include but not limited to:
1. Defined roles for metabolic pathways or metabolites in immune cell function related to homeostasis inflammation or immune-oncology.
2. Rationale and evidence for new pharmacological targets for the treatment of disease.
3. Impact of aging on immunometabolism and immune cell function.
4. Links between nutrition, metabolic pathways and immune cell function in health and disease.
5. Association studies linking therapies that target metabolism to immune cell function.
Image credits: Peter Bunyard (Created with BioRender.com)
Dr. Marina Makrecka-Kuka has 15 year-experience in energy metabolism research and drug discovery projects. She has degree in Pharmacy and a PhD in Pharmaceutical Pharmacology (obtained in 2015) from Riga Stradins University (Latvia). Since undergraduate studies Marina has worked at Laboratory of Pharmaceutical Pharmacology at Latvian Institute of Organic Synthesis, where she was leading immunometabolism and mitochondrial physiology research as well as drug discovery related studies of energy metabolism. She contributed to the development of drug candidates that had successfully reached clinical trials. During scientific career Marina published more than 50 scientific papers in metabolism field and contributed to 3 Patent Cooperation Treaty applications related to discovery of novel compounds targeting energy metabolism. Marina has been active member of Mitochondrial Physiology Society and regional societies of Biochemistry and Pharmacology, as well as Scientific communication manager in the couple of European research and networking projects. In 2022 Marina changed career path and moved to Sitryx Therapeutics a biotech developing new immunometabolism therapies, where she is Senior Scientist and acts as internal expert in metabolism field.