Immunometabolic Reprogramming in Pediatric Acute Lymphoblastic Leukemia: A Systematic Review of Blast-Intrinsic Metabolism, the Bone-Marrow Niche, and Immune-Cell Fitness

Abstract

Jacopo Martelli*

Background: Acute lymphoblastic leukemia (ALL) is the most common malignancy of childhood. Although cure rates now exceed 85%, relapse and treatment-related toxicity remain major problems, and both are increasingly linked to how leukemic blasts, the bone-marrow niche and surrounding immune cells reprogram their metabolism. “Immunometabolic reprogramming” — the coupling of oncogene-driven metabolic rewiring in blasts to the metabolic suppression of effector immune cells — has emerged as a unifying framework linking drug resistance to immune escape.

Methods: We performed a systematic review following PRISMA 2020. Bibliographic databases and supplementary sources were searched for studies examining metabolic or immunometabolic phenotypes in pediatric ALL. Forty studies met predefined eligibility criteria and were synthesized qualitatively and mapped by metabolic pathway, lineage (B- vs T-ALL) and study design.

Results: Convergent evidence shows that B-ALL blasts operate under transcription-factor (PAX5/IKZF1) restraint of glucose uptake, whereas oncogenic lesions (notably NOTCH1 in T-ALL) drive glutamine-fueled and mitochondrial anabolism. Amino-acid dependencies (asparagine, glutamine, arginine) underlie the activity of, and resistance to, L-asparaginase, with adipocytes and mesenchymal stromal cells providing metabolic rescue. In parallel, the leukemic niche depletes glucose, arginine and tryptophan and engages immunosuppressive programs (e.g. IDO1), contributing to naive-T-cell deficits at diagnosis that compromise the fitness of autologous CAR-T products. Preclinical and early- clinical agents target glycolysis, glutaminolysis, fatty-acid oxidation, mitochondrial complex I and amino-acid depletion, and metabolically armored immune cells are in development.

Conclusions: Metabolism and immunity in pediatric ALL are mechanistically inseparable. Targeting shared metabolic nodes offers an opportunity to simultaneously sensitize blasts and rescue immune-effector function, but pediatric- specific, lineage-resolved and developmentally aware studies are needed before immunometabolic therapy enters the clinic for children.

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