Emerging immune checkpoints in the tumor microenvironment: Implications for cancer immunotherapy

Immune checkpoints within the tumor microenvironment (TME) play important roles in modulating host antitumor immunity. Checkpoint-based immunotherapies (e.g. immune checkpoint inhibitors) have revolutionized cancer therapy. However, there are still many drawbacks with current checkpoint immunotherapies in clinical practice, such as unresponsiveness, resistance, tumor hyperprogression, autoimmune-related adverse events, and limited efficacy with some solid malignances. These drawbacks highlight the need to further investigate the mechanisms underlying the therapeutic effects, as well as the need to identify new targets for cancer immunotherapy. With the discovery of emerging immune checkpoints in the TME, the development of strategies targeting the pivotal immunomodulators for cancer treatment has been significantly advanced in the past decade. In this review, we summarize and classify the novel emerging immune checkpoints beyond the extensively studied ones (e.g. PD-1, PD-L1, CTLA-4, LAG-3 and TIM-3) in the TME, and provide an update on the clinical trials targeting these key immune molecules.