**1. Introduction**

Cancer immunotherapy is a promising strategy to combat cancer by leveraging host immune system, involving lymphocyte-promoting cytokines, cancer vaccines, immune checkpoint therapy (ICT), and engineered T cells [1, 2]. Among the diverse immunotherapeutic approaches, ICT is the most thoroughly investigated approach with broad impact. It can enhance antitumor immunity by inhibiting negative regulatory pathways. To date, several monoclonal antibodies against the cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death 1 (PD1)–PD1 ligand 1 (PD-L1) axis have been clinically approved for various cancers, including melanoma, lung, and renal cancers (**Figure 1**) [3]. Some other checkpoint inhibitors are also in preclinical or earlier phases of clinical development, such as LAG3, TIGIT, TIM3, B7H3, CD39, CD73 and adenosine A2A receptors [4, 5].

Despite substantial progress of immune checkpoint inhibitors (ICIs) in the cancer treatment, there are still several key limitations. Firstly, systemically delivery of checkpoint inhibitors may cause serious side effects in several major organs.

#### **Figure 1.**

*Timeline of significant milestones in the development of cancer immune checkpoint inhibitors. CD28: cluster of differentiation 28; CTLA-4: cytotoxic T lymphocyte-associated protein 4; FDA: US Food and Drug Administration; irRC: immune-related response criteria; PD-1: programmed cell death protein 1; and Tregs: regulatory T cells.*

In addition, many patients with nonimmunogenic tumor microenvironments (TMEs) showed therapeutic resistance to checkpoint inhibitors and do not respond to the treatment. The mechanism of the non-responsiveness to checkpoint inhibitors are still in investigation and may involve poor tumor-infiltration of T cells, checkpoints dysregulation in tumor cells and T cells, and adaptive resistance to checkpoint inhibition [6–8]. These drawbacks need to be overcome to achieve more satisfactory therapeutic outcomes against various cancer. In this chapter, we will introduce immunological mechanism of immune checkpoint blockade and highlight emerging approaches to enhancing ICT efficiency. It is foreseeable that ICT will lead to next-generation promising techniques and continuously contribute to the future cancer treatment.
