Abstract 4365153: Dysregulated Lactate Metabolism in Cardiomyocytes Drives Immune Checkpoint Inhibitor- Associated Myocarditis

Introduction: Immunotherapy have significantly improved cancer patient survival，but cardiovascular diseases increasingly contribute to mortality in these patients. Although PD-1 inhibitor-associated cardiotoxicities are rare, they exhibithigh mortality. The lack of biomarkers and targeted therapies underscores an urgent need to elucidate their molecular mechanisms. Methods and Results: We established mouse models of transplanted tumors and autoimmune myocarditis. Anti-PD-1 was administered to both tumor-bearing and littermate control groups. Tumor-bearing mice exhibited exacerbated myocardial injury versus controls, as demonstrated by echocardiography, increased cardiac fibrosis, and elevated cardiac immune cell infiltration. Based on the results of Positron emission tomography-Computed tomography (PET–CT), lactate fluorescent probes, Seahorse assays, and in vivo imaging. Cardiac fatty acid uptake and oxidation capacity were significantly reduced by tumor burden, while compensatory lactate utilization was enhanced. Furthermore, anti-PD-1 treatment was observed to disrupt lactate metabolic equilibrium. Moreover, cardiomyocyte-specific Monocarboxylate transporter 1 (MCT1) knockout mice were constructed to reduce lactate uptake in cardiomyocytes, which exacerbated PD-1-induced myocardial injury. Conversely, sodium lactate supplementation was demonstrated to alleviate cardiac dysfunction. Mechanistically, tumor cells induce increased expression of MCT1 in cardiomyocytes and elevated intracellular lactate levels by secreting growth factors and excessive lactate. Overexpression of MCT1 in cardiomyocytes leads to increased lactate uptake, which inhibits fatty acid metabolism while promoting ROS accumulation, causing mitochondrial dysfunction and mtDNA release. Concurrently, lactate suppressed inflammatory gene expression via lactylation-mediated cGAS inhibition, establishing metabolic-immune balance. Anti-PD-1 treatment disrupts this equilibrium and caused metabolic disorder by reducing cardiomyocyte lactate availability, resulting in cGAS reactivation and subsequent triggering of the cGAS-STING pathway-mediated inflammatory cascade, ultimately culminating in inflammatory amplification. Conclusion: Our study uncovers a tumor-induced shift in myocardial metabolism and immunometabolic balance, wherein anti-PD-1 disrupts lactate homeostasis, triggering cGAS-STING-mediated inflammation and myocarditis. Key Words: ICI-myocarditis; MCT1; Myocardial metabolism; PD-1