Nicotinamide Metabolism Constrains Memory CD8 + T Cell Formation Through a Putative HS1BP3‐SIRT1‐FOXO3‐BCL6 Axis

ABSTRACT Memory T cells exhibit long‐term persistence, a defining feature that underpins durable clinical responses to adoptive immunotherapies. The mechanisms that integrate metabolic cues with transcriptional control of memory fate remain undetermined. Here, we identify HS1‐binding protein 3 (HS1BP3) is preferentially expressed in memory CD8 + T cells. HS1BP3 deficiency reduced memory‐associated gene expression in CD8 + OT‐1 T cells following Listeria monocytogenes– ovalbumin infection and impaired antitumor responses. Loss of HS1BP3 induces metabolic reprogramming characterized by reduced oxidative phosphorylation (OXPHOS) and altered nicotinamide metabolism, accompanied by increased NAD + and nicotinamide metabolite 1‐methylnicotinamide (MNAM) abundance. HS1BP3 interacted with Sirtuin 1 (SIRT1), and its deficiency is associated with increased SIRT1 activity, enhanced Forkhead box O3 (FOXO3) signaling, and reduced expression of memory‐associated transcription factor B cell lymphoma 6 (BCL6). Moreover, accumulation of MNAM impairs the antitumor activity of CD8 + T cells. Importantly, elevated levels of HS1BP3 drive chimeric antigen receptor (CAR) ‐T cells towards a memory phenotype and improve tumor control. Collectively, our findings identify HS1BP3 as a regulator of CD8 + T cell memory and indicate that its effects are associated with alterations in nicotinamide metabolism and the SIRT1–FOXO3–BCL6 signaling axis. These observations support the therapeutic potential of HS1BP3‐engineered CAR‐T cells across solid tumors.