Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation

Simple Summary Targeting amino acid metabolism in leukemia therapy presents both opportunities and challenges. While disrupting amino acid utilization can hinder cancer cell growth and enhance treatment efficacy, achieving selective targeting to minimize damage to healthy cells is crucial. This review explores novel strategies for amino acid depletion-based treatments in leukemia, highlighting the potential of combining these approaches with traditional chemotherapeutics and immunotherapies to overcome resistance and improve patient outcomes.Abstract Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.