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

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.