Immune checkpoint inhibitors (ICI) have emerged as a remarkable treatment option for diverse cancer types. Currently, ICIs are approved for an expanding array of cancer indications. However, the majority of patients still do not demonstrate a durable long-term response following ICI therapy. In addition, many patients receiving ICI therapy develop immune-related adverse events (irAEs) affecting a wide variety of organs. To increase the percentage of patients who benefit from ICI therapy and to reduce the occurrence of irAEs, there is an ongoing effort to combine current ICIs with novel checkpoints inhibitors or other therapeutic approaches to achieve a synergistic effect which is larger than the sum of its parts.

In this review we highlight the essential factors for more effective ICI combinations. We describe how the design of these strategies should be driven by the tumor's immunological context. We analyze current combination strategies and describe how they can be improved to unleash the immune system's full anti-cancer potential as well as convert immunologically "cold" tumors into "hot" ones. We examine the efforts to combine current ICIs (PD-1 and CTLA-4) with novel checkpoints (TIM-3, LAG-3, VISTA, TIGIT and others), immunotherapies (CAR-T cells and Cancer Vaccines) and delivery strategies (bispecific antibodies and other delivery platforms). Importantly, we outline how can one optimally combine ICIs with traditional pillars of cancer therapy such as radiation therapy (RT) and chemotherapy. We discuss the considerations regarding successful combination with RT and chemotherapy; these include fractionation schemes and selection of chemotherapeutics which can both directly eradicate cancer cells as well as increase the infiltration of immune cells into tumors. Finally, we critically assess these approaches and attempt to establish their strengths and weaknesses based on pre-clinical and clinical data.

免疫检查点抑制剂（ICI）已经成为多种癌症类型的出色治疗选择。当前，ICI被批准用于越来越多的癌症适应症。但是，大多数患者在ICI治疗后仍未表现出持久的长期反应。此外，许多接受ICI治疗的患者会发生免疫相关的不良事件（irAE），影响多种器官。为了增加受益于ICI治疗的患者的百分比并减少irAE的发生，正在努力将当前的ICI与新型检查点抑制剂或其他治疗方法结合使用，以产生大于其总和的协同效应。 。

在本文中，我们重点介绍了更有效的ICI组合的必要因素。我们描述了如何由肿瘤的免疫学背景驱动这些策略的设计。我们分析了目前的联合策略，并描述了如何改进它们以释放免疫系统的全部抗癌潜能，以及将免疫学上“冷”的肿瘤转化为“热”的肿瘤。我们研究了将目前的ICI（PD-1和CTLA-4）与新型检查点（TIM-3，LAG-3，VISTA，TIGIT等），免疫疗法（CAR-T细胞和癌症疫苗）和给药策略（双特异性抗体和其他递送平台）。重要的是，我们概述了如何最佳地将ICI与传统的癌症疗法（例如放射疗法（RT）和化学疗法）结合起来。我们讨论了成功与放疗和化疗联合使用的注意事项；这些措施包括分级方案和化学疗法的选择，它们既可以直接根除癌细胞，又可以增加免疫细胞向肿瘤的浸润。最后，我们严格评估这些方法，并尝试根据临床前和临床数据确定其优缺点。