Cancer immunotherapies, represented by immune checkpoint inhibitors (ICIs), have reshaped the treatment paradigm for both advanced non-small cell lung cancer and small cell lung cancer. Programmed death receptor-1/programmed death receptor ligand-1 (PD-1/PD-L1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) are some of the most common and promising targets in ICIs. Compared to ICI monotherapy, which occasionally demonstrates treatment resistance and limited efficacy, the dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 operates at different stages of T cell activation with synergistically enhancing immune responses against cancer cells. This emerging dual therapy heralds a new direction for cancer immunotherapy, which, however, may increase the risk of drug-related adverse reactions while improving efficacy. Previous clinical trials have explored combination therapy strategy of anti-PD-1/PD-L1 and anti-CTLA-4 agents in lung cancer, yet its efficacy remains to be unclear with the inevitable incidence of immune-related adverse events. The recent advent of bispecific antibodies has made this sort of dual targeting more feasible, aiming to alleviate toxicity without compromising efficacy. Thus, this review highlights the role of dual blockade immunotherapy targeting PD-1/PD-L1 and CTLA-4 in treating lung cancer, and further elucidates its pre-clinical mechanisms and current advancements in clinical trials. Besides, we also provide novel insights into the potential combinations of dual blockade therapies with other strategies to optimize the future treatment mode for lung cancer.

中文翻译：

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肺癌中靶向 PD-1/PD-L1 和 CTLA-4 的双重封闭免疫疗法


以免疫检查点抑制剂 （ICI） 为代表的癌症免疫疗法重塑了晚期非小细胞肺癌和小细胞肺癌的治疗模式。程序性死亡受体-1/程序性死亡受体配体-1 （PD-1/PD-L1） 和细胞毒性 T 淋巴细胞相关抗原-4 （CTLA-4） 是 ICI 中最常见和最有前途的靶点。与偶尔表现出治疗耐药性和疗效有限的 ICI 单一疗法相比，靶向 PD-1/PD-L1 和 CTLA-4 的双重封闭免疫疗法在 T 细胞活化的不同阶段起作用，协同增强对癌细胞的免疫反应。这种新兴的双重疗法预示着癌症免疫疗法的新方向，然而，这可能会增加药物相关不良反应的风险，同时提高疗效。既往临床试验探讨了抗 PD-1/PD-L1 和抗 CTLA-4 药物在肺癌中的联合治疗策略，但其疗效仍不清楚，免疫相关不良事件的发生不可避免。最近双特异性抗体的出现使这种双重靶向更加可行，旨在减轻毒性而不影响疗效。因此，本文重点介绍了靶向 PD-1/PD-L1 和 CTLA-4 的双重阻断免疫疗法在治疗肺癌中的作用，并进一步阐明了其临床前机制和临床试验的最新进展。此外，我们还为双重阻断疗法与其他策略的潜在结合提供了新的见解，以优化肺癌的未来治疗模式。