Immune checkpoint blockade (ICB) has shown improvement in overall survival for lung cancer in clinical trials. However, monotherapies have limited efficacy in improving outcomes and benefit only a subset of patients. Combination therapies targeting multiple pathways can augment an immune response to improve survival further. Here, we demonstrate that combinatorial anti-PD-L1/cryoablation therapy generated a synergistic antitumor activity in the established lung cancer model. Importantly, it was observed that this favorable antitumor immune response comes predominantly from the PD-1+CD8+ T cells generated after the combination therapy, referred as improvement of IFN-γ production and mitochondrial metabolism, which resembled highly functional effectors CD8+ T cells. Notably, the cellular levels of mitochondrial reactive oxygen and mitochondria mass excessively coincided with alteration of IFN-γ secretion in PD-1+CD8+T cell subset. So far, anti-PD-L1/cryoablation therapy selectively derived the improvement of depolarized mitochondria in PD-1+CD8+T cell subset, subsequently rebuild the anti-tumor function of the exhausted CD8+ T cells. Collectively, there is considerable interest in anti-PD-L1 plus cryoablation combination therapy for patients with lung cancer, and defining the underlying mechanisms of the observed synergy.

临床试验显示，免疫检查点阻断（ICB）可改善肺癌的总体生存率。然而，单一疗法在改善预后方面的功效有限，并且仅使一小部分患者受益。针对多种途径的联合疗法可以增强免疫反应，进一步提高生存率。在这里，我们证明抗 PD-L1/冷冻消融组合疗法在已建立的肺癌模型中产生了协同抗肿瘤活性。重要的是，据观察，这种有利的抗肿瘤免疫反应主要来自联合治疗后产生的 PD-1+CD8+ T 细胞，称为 IFN-γ 产生和线粒体代谢的改善，类似于功能强大的效应 CD8+ T 细胞。值得注意的是，线粒体活性氧和线粒体质量的细胞水平与 PD-1+CD8+T 细胞亚群中 IFN-γ 分泌的变化过度一致。迄今为止，抗PD-L1/冷冻消融疗法选择性地诱导PD-1+CD8+T细胞亚群中去极化线粒体的改善，从而重建耗竭的CD8+T细胞的抗肿瘤功能。总的来说，人们对肺癌患者的抗 PD-L1 联合冷冻消融联合疗法非常感兴趣，并确定了所观察到的协同作用的潜在机制。