Immune Checkpoint Inhibitors in Cancer Therapy-How to Overcome Drug Resistance?

Abstract

Immune checkpoint inhibitors (ICIs), antagonists used to remove tumor suppression of immune cells, have been widely used in clinical settings. Their high antitumor effect makes them crucial for treating cancer after surgery, radiotherapy, chemotherapy, and targeted therapy. However, with the advent of ICIs and their use by a large number of patients, more clinical data have gradually shown that some cancer patients still have resistance to ICI treatment, which makes some patients unable to benefit from their antitumor effect. Therefore, it is vital to understand their antitumor and drug resistance mechanisms. In this review, we focused on the antitumor action sites and mechanisms of different types of ICIs. We then listed the main possible mechanisms of ICI resistance based on recent studies. Finally, we proposed current and future solutions for the resistance of ICIs, providing theoretical support for improving their clinical antitumor effect.

Keywords: immune checkpoint inhibitors; immunotherapy; resistance.

Figure 1

Summary of immune checkpoints in different immune cells and tumor cells. Each ICI was targeted to different cell types. Although two of the ICIs’ target receptors and corresponding ligands are in the same checkpoint signaling pathway, there are also differences in therapeutic efficacy and side effects between them. In addition, there may be overlapping inhibitory effects between different checkpoint signaling pathways in the same immune cell type. This is one of the reasons for ICI resistance.

Figure 2

Different therapeutic strategies for overcoming drug resistance with ICIs. There are two main strategies for improving ICI therapy effectiveness and reducing the number of patients with ICI resistance. The first strategy is to improve immune cell infiltration in TME by some cytokines or chemokines, and enhance T cell recognition for tumor cells. The second strategy is to increase the concentration of tumor antigens in THE TME by biological, physical, or chemical methods to facilitate antigen presentation by APC. In addition, the combination of different ICI types may also produce synergistic antitumor effects.