The gastrointestinal microbiome and constituent short-chain fatty acids: a narrative review of an underexplored axis in acute lymphoblastic leukemia

Acute Lymphoblastic Leukemia (ALL) is an aggressive malignancy of lymphoid progenitors, and remains the most commonly diagnosed hematological cancer in the pediatric population. Although 5-year overall survival rates now exceed 90%, standard-of-care therapies are associated with substantial acute and long-term toxicities, underscoring the need for novel and supportive strategies that preserve treatment efficacy whilst reducing dose-limiting side effects. Increasing evidence linking the microbiome to therapeutic response and toxicity in oncology highlights the potential relevance of microbial-derived metabolites, particularly short-chain fatty acids (SCFAs), in hematological malignancies. This review critically examines the emerging, yet limited, evidence supporting a role for SCFAs in ALL, integrating mechanistic insights from metabolic, immunological, and oncological studies to propose biologically plausible pathways of involvement. Specifically, we suggest how SCFAs may influence treatment response, mitigate therapy-related toxicity, reduce treatment-related morbidity and modulate early-life factors associated with ALL risk. Whilst direct ALL-specific evidence remains sparse, we propose that SCFAs represent a compelling and underexplored axis for microbiome-ALL research, and we aim to stimulate targeted experimental and clinical investigations to define their therapeutic potential.