Amino acid metabolic reprogramming drives pathogenesis and therapy in hematologic malignancies.

Hematological malignancies exhibit distinct patterns of amino acid metabolic reprogramming, which support uncontrolled proliferation, immune escape, and therapy resistance. Rather than merely fueling biosynthesis, amino acid metabolism intricately modulates tumor progression and therapeutic responses through interactions with signaling pathways such as mTOR, β-catenin/c-Myc, and NF-κB. This review emphasizes the rewired utilization of key amino acids-including glutamine, arginine, leucine, tryptophan, and phenylalanine-across leukemia, lymphoma, and multiple myeloma, and discusses how these changes orchestrate immune suppression and redox imbalance. Emerging studies reveal that metabolic vulnerabilities can be therapeutically exploited via enzyme depletion, transport inhibition, or combination regimens with immunotherapies and mTOR inhibitors. Moreover, amino acid-driven drug resistance mechanisms, particularly involving stromal support and transcriptional reprogramming, pose both challenges and opportunities for next-generation treatment design. By decoding the complex metabolic-immune-tumor network, we highlight strategic interventions that leverage amino acid metabolism as a therapeutic axis in hematological cancers.