Modulation of Nociceptive Nerve Activity as a Novel Therapeutic Strategy in Acute Myeloid Leukemia

• AML remodels the neural microenvironment early in disease progression • Leukemic cells preferentially accumulate in neural-sparse regions in bone marrow • Pharmacological ablation of nociceptive nerves accelerates leukemic progression and disrupts stressed hematopoiesis • Activation of nociceptive nerves by dietary capsaicin delayed AML onset and improved overall survival Emerging evidence has highlighted a critical role of the neuro-microenvironment in regulating hematopoiesis and hematologic malignancies. However, how malignant cells remodel the neural compartment and how these neural changes in turn influence disease progression remain poorly understood. In this study, we mapped the spatial distribution of sympathetic (TH + ) and nociceptive (CGRP + ) nerve fibers in the bone marrow and spleen under steady-state conditions and during acute myeloid leukemia (AML) using immunofluorescence imaging. We found that AML induces a reduction of nerve fiber density at the early stage of AML and that leukemic cells preferentially accumulate in neural-sparse regions. Functional investigations revealed that pharmacological ablation of nociceptive nerves via capsaicin accelerated leukemic progression and disrupted stressed hematopoiesis. Conversely, activation of nociceptive nerves by dietary capsaicin delayed AML onset and improved overall survival. Further mechanistic investigation revealed that the CGRP–RAMP1 axis inhibits leukemia progression by suppressing the TNF-α pathway in AML cells. These findings highlight the anti-leukemic role of nociceptive nerves and suggest therapeutic potential for neural modulation in AML.