Nicotinamide prevents anti-PD1 immune checkpoint inhibitor-associated early stages of cardiotoxicity.

Cardiac immune-related adverse events (irAEs) associated with anti-programmed death-1 (anti-PD1) immune checkpoint inhibitors (ICIs) are of major concern, as they can be fatal; however, their underlying molecular mechanisms remain poorly understood. In this study, we retrospectively investigated the role of anti-PD1 ICIs in the early stages of cardiotoxicity and the underlying mechanisms. We conducted in vitro and vivo experiments to investigate the underlying mechanisms. The hearts of male mice and HL-1 cells showed downregulated myocardial apolipoprotein A (Apoa) 1 and Apoa2 expression following anti-PD1 therapy. BATF transcriptionally activated Apoa1 and Apoa2 expression, and recombinant Apoa1/Apoa2 markedly improved cardiac function in anti-PD1-treated and PD1-knockout mice. Additionally, anti-PD1 therapy induced the myocardial infiltration of macrophages in male mice. These findings showed that nicotinamide could potentially preserve the left ventricular ejection fraction (LVEF) without compromising the anticancer efficacy of anti-PD1 therapy. Mechanistically, nicotinamide altered myocardial lipid metabolism and reduced the inflammation induced by anti-PD1 therapy. Findings from the randomized controlled trial involving twelve patients with cancer treated with anti-PD1 therapy confirmed a slight decrease in the LVEF and a marked increase in myocardial enzyme levels. Nicotinamide treatment effectively mitigated these changes compared with those observed in the control group. Our findings contribute to a better understanding of cardiac anti-PD1 irAEs and show that nicotinamide might be a promising preventive strategy in the early stages of anti-PD1 ICI-associated cardiotoxicity.