Background: Immune checkpoint inhibitors (ICIs) are a new anti-cancer therapy that have improved survival rates in many aggressive cancers. However, while rare, a significant number of patients develop ICI-induced cardiotoxicity. Clinical manifestations are non-specific and underlying cellular mechanisms remain unknown, making diagnosis and treatment of these ICI-induced cardiac side effects difficult. Exercise has shown protective effects against chemotherapy-induced cardiotoxicity but has not been investigated in combination with ICIs. High-intensity exercise has shown greatest cardioprotective effects in preclinical (animal) models, but human cancer patients prefer low-intensity exercise in the clinical setting. Therefore, the purpose of this study was to further identify the cardioprotective effects of low-intensity exercise as a treatment strategy against ICI-induced cardiotoxicity. Methods: Female mice were randomly selected and separated into four groups: sedentary (SED), sedentary ICI-treated (SED + ICI), low-intensity treadmill-exercised (TM), and low-intensity treadmill-exercised ICI-treated mice (TM + ICI). Mice either underwent a 4-week low-intensity treadmill exercise protocol (TM) or remained sedentary (SED). During the 4 weeks, ICI mice received anti-PD-1 treatment (200 μg/mouse) via intraperitoneal injections twice each week. Echocardiography was performed at baseline and sacrifice to determine changes in cardiac structure and function. At sacrifice, cardiac tissue was collected, weighed, and frozen for further biochemical analysis. Underlying metabolic signaling pathways were assessed via Western Blot, and autophagic flux was analyzed via fluorescent microscopy. Results: Echocardiography at sacrifice revealed significantly decreased fractional shortening as a measure of cardiac function (−20%), 1.5-fold dilation of the left ventricle, and thinning of the posterior cardiac wall at systole and diastole in SED + ICI mice compared to SED controls (p< 0.05), indicative of a phenotype of ICI-induced dilated cardiomyopathy. TM + ICI mice did not show a significant difference in these cardiac structural and functional parameters, suggesting cardioprotective effects of low-intensity exercise. In line with these findings, Western Blot and fluorescent microscopy analyses revealed upregulation of autophagic flux (p< 0.05), as well as dysfunctional metabolic pathways (p< 0.05) in ICI-treated mice compared to non-ICI controls. Low-intensity exercise was associated with regulation of dysfunctional metabolism and autophagy in TM + ICI compared to SED + ICI mice. Conclusions: The clinically relevant ICI treatment protocol used in this study led to significant cardiac dysfunction and remodeling, accompanied by underlying dysfunctional metabolism and autophagy. Low-intensity exercise was capable of regulating abnormal protein synthesis and degradation and protecting against ICI-induced cardiotoxicity. This study adds knowledge to the characterization of still unclear clinical manifestations of ICI-induced cardiotoxicity, underlying signaling pathways that could shed light on potential pharmacological treatment targets, as well as the protective effects of low-intensity exercise as a non-pharmacological treatment strategy.
背景：免疫检查点抑制剂（ICIs）作为一种新型抗癌疗法，已显著提高多种侵袭性癌症患者的生存率。然而，尽管发生率较低，仍有相当数量的患者出现ICI诱导的心脏毒性。其临床表现缺乏特异性，且潜在的细胞机制尚不明确，导致此类心脏副作用的诊断与治疗面临挑战。运动已被证实对化疗诱导的心脏毒性具有保护作用，但其与ICIs联合应用的效果尚未得到研究。临床前（动物）模型显示高强度运动具有最佳的心脏保护效果，但临床环境中癌症患者更倾向于低强度运动。因此，本研究旨在进一步探讨低强度运动作为对抗ICI诱导心脏毒性的治疗策略所发挥的心脏保护作用。 方法：将雌性小鼠随机分为四组：静息组（SED）、静息ICI治疗组（SED+ICI）、低强度跑台运动组（TM）及低强度跑台运动ICI治疗组（TM+ICI）。小鼠接受为期4周的低强度跑台运动方案（TM）或保持静息状态（SED）。在4周干预期间，ICI治疗组小鼠每周接受两次腹腔注射抗PD-1治疗（200 μg/只）。于基线期和处死前通过超声心动图检测心脏结构与功能变化。处死后采集心脏组织进行称重、冷冻保存及后续生化分析。通过蛋白质印迹法评估潜在代谢信号通路，并利用荧光显微镜分析自噬流变化。 结果：处死前超声心动图显示，与SED对照组相比，SED+ICI组小鼠心脏功能指标缩短分数显著降低（−20%），左心室扩张1.5倍，收缩期与舒张期后壁变薄（p<0.05），呈现ICI诱导的扩张型心肌病表型。而TM+ICI组小鼠的心脏结构与功能参数未见显著差异，提示低强度运动具有心脏保护作用。与此一致，蛋白质印迹与荧光显微镜分析显示，与非ICI对照组相比，ICI治疗组小鼠自噬流上调（p<0.05）且代谢通路功能紊乱（p<0.05）。低强度运动与TM+ICI组（相较于SED+ICI组）紊乱的代谢和自噬调控相关。 结论：本研究所采用的临床相关ICI治疗方案可导致显著的心功能障碍与重构，并伴随潜在的代谢紊乱和自噬异常。低强度运动能够调节异常的蛋白质合成与降解过程，并对抗ICI诱导的心脏毒性。本研究增进了对尚不明确的ICI诱导心脏毒性临床表现特征的认识，揭示了可能作为潜在药物治疗靶点的信号通路，同时论证了低强度运动作为非药物治疗策略的保护作用。
肿瘤(癌症)患者之家