NAD+ precursor supplementation reverses CD36-mediated lipid accumulation and ferroptosis to restore antitumor function of NK cells in DLBCL

Natural killer (NK) cells play a key role in the standard treatment of diffuse large B-cell lymphoma (DLBCL). However, NK cells in DLBCL patients frequently display an exhausted phenotype, which is associated with poor clinical outcomes. The metabolic mechanisms contributing to this functional impairment remain poorly understood. We assessed degranulation (CD107a), cytokine secretion (IFN-γ, TNF-α), mitochondrial activity, and lipid metabolism in NK cells from DLBCL patients and healthy donors. Dysregulated lipid species were identified by GC-MS lipidomics and validated in NK-92MI and primary NK cells. The functional involvement of CD36 was assessed using the specific inhibitor, with subsequent examination of its correlation with cytotoxic activity. NAD + metabolism was evaluated via NAMPT and NAD + levels, and rescue assays involved nicotinamide mononucleotide (NMN). For in vivo validation, a murine lymphoma model was treated with nicotinamide riboside (NR), and tumor-infiltrating NK cell function and lipid accumulation were analyzed. NK cells from DLBCL patients demonstrated significantly reduced proliferative capacity and cytotoxicity, accompanied by substantial lipid accumulation. This dysfunction was linked to upregulated CD36 expression and associated with ferroptosis—a form of regulated necrotic cell death. Mechanistically, CD36-mediated lipid uptake induced metabolic reprogramming and promoted ferroptotic cell death, concurrently depleting intracellular NAD + levels. Importantly, supplementation with NAD + precursors effectively reversed NK cell exhaustion and restored antitumor activity both in vitro and in vivo .CD36-driven lipid metabolic disruption leads to NK cell dysfunction and ferroptosis in DLBCL. Thus, restoration of NAD + levels represents a promising therapeutic strategy to enhance NK cell effector function and improve antitumor immunity in DLBCL. • Lipid accumulation and lipid peroxidation increase in NK cells from DLBCL patients • CD36 overexpression induces FFA transport in NK cells • NAD+ supplementation inhibits lipid accumulation and restores the effector function of NK cells