Tumor-secreted BDNF selectively depletes macrophage NAD+ via CD73 upregulation to suppress antitumor immunity

Abstract Intracellular nicotinamide adenine dinucleotide (NAD+) plays a pivotal role in linking cellular metabolic states to immune cell function, positioning NAD+ boosting as a promising immunotherapy strategy. However, whether a targetable NAD+ metabolic vulnerability exists within the tumor immune microenvironment remains poorly understood. Herein, we discover a novel metabolic crosstalk between tumor cells and macrophages that leads to specific NAD+ depletion in M1-like macrophages, resulting in a metabolic vulnerability that can be therapeutically exploited to enhance antitumor immunity. We demonstrate that brain-derived neurotrophic factor (BDNF) secreted by tumor cells upregulates CD73 expression in macrophages. By coupling to CD38 in M1-like macrophages, CD73 mediates selective intracellular NAD+ depletion, inducing a senescence associated secretory phenotype (SASP) that facilitates tumor immune evasion. Pharmacological activation of nicotinamide phosphoribosyltransferase (NAMPT) restores NAD+ levels in M1-like macrophages and sensitizes tumors to programmed cell death 1 receptor (PD-1) blockade. Importantly, NAMPT activator confines NAD+ elevation to M1-like macrophages, avoiding the systemic effects associated with the NAD+ precursor NMN supplementation. Together, our findings reveal a previously unrecognized tumor-macrophage interplay mediated by the BDNF-CD73 axis in reprogramming NAD+ metabolism and highlight NAMPT activation as a specific NAD+ boosting strategy to reinvigorate antitumor immunity.