Biological and Analytical Perspectives on D-Amino Acids in Cancer Diagnosis and Therapy

For a long time, D-amino acids remained unexplored in mammalian physiology. The technological advances in enantioseparation over the past 50 years have revealed that D-amino acids not only exist in human tissues and fluids but also play important roles in neurotransmission, immune regulation, and cellular proliferation. The present review provides a comprehensive assessment of the role of D-amino acids in cancer, including their endogenous and exogenous production pathways, along with the analytical methodologies used for detection and quantification, from liquid chromatography to biosensors. These methods have underlined how altered levels of D-amino acids can be helpful in early detection, progression, or response to treatment in several malignancies, including gastric, hepatic, colorectal, or breast cancer. The present review also explores how manipulation of D-amino acids can regulate cell proliferation, their mechanisms in cancer regulation, including the modulation of N-methyl-D-aspartate (NMDA) receptors and the production of hydrogen sulphide (H₂S), and the role of specific D-amino acids in cancer onset, immune defence, and protection against chemotherapy-induced toxicity. Finally, several underexplored research directions are outlined, such as potential correlations with gut microbiota composition, the impact of processed food consumption, and the integration of multiomics strategies.