Anti-PD-1 immune checkpoint inhibitor-induced cardiotoxicity is associated with dysfunctional metabolism, muscle wasting and autophagy

Immune checkpoint inhibitors (ICIs)have significantly improved overall survival rates in many aggressive cancers. Despite the recent clinical success, a rapidly increasing number of patients suffer from ICI-induced cardiotoxicity with often fatal outcomes, nonspecific symptoms and uninvestigated underlying pathological mechanisms. Therefore, this study explored metabolic, muscle wasting, and autophagic pathways and their roles in ICI-induced cardiac remodeling and dysfunction. Female C57BL/6 wildtype and LC3 transgenic (autophagy reporter) mice were randomly assigned to control (CON) and ICI-treated (ICI) groups. Mice underwent 4 weeks of ICI treatment (200 µg/mouse, intraperitoneally, twice/week). Echocardiography assessed ICI-induced changes in cardiac structure and function. At euthanasia, cardiac tissue was collected for Western Blot analysis of metabolic and muscle wasting signaling pathways and confocal fluorescent microscopy of autophagic flux. ICI treatment reduced tumor burden (-48% mass, P < 0.05) and led to significantly decreased cardiac function (-20%) and remodeling, including left ventricular dilation (+ 50%) and thinning of posterior cardiac walls (P < 0.05), indicative of dilated cardiomyopathy. Exploratory protein level analysis revealed dysfunctional muscle wasting (Atrogin1, MuRF1) disrupted AKT and FoxO1 signaling, and altered autophagic flux (P < 0.05). In this model, ICI-induced cardiotoxicity was characterized by severe cardiac remodeling and dysfunction, associated with dysfunctional metabolism, muscle wasting, and autophagy. To our knowledge, this is one of the first studies to explore underlying pathological mechanisms, adding novel and impactful insight to the still unclear characteristics of ICI-induced cardiotoxicity and supporting the critical need to further investigate side effects of immunotherapies to optimize clinical treatment of cancers.