Cancer immunotherapy has recently shown promising antitumor effects in various types of tumors. Among all immune checkpoints, the PD-1/PD-L1 pathway plays an important role in the immune evasion of tumor cells, making it a potent target in antitumor immunity. Accordingly, antibodies targeting the PD-1/PD-L1 pathway have been developed to attack tumor cells; however, resistance to immune therapy remains to be solved. Hence, identification of the underlying modulators of the PD-1/PD-L1 pathway is of significant importance to understand the mechanisms of antitumor immunotherapy. Long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs) have been identified to regulate the PD-1/PD-L1 pathway, leading to participation in the immune response and immunotherapy. Therefore, this review focuses on the functions of lncRNAs and circRNAs in regulation of the PD-1/PD-L1 axis in tumorigenesis and tumor progression. We hope this review will stimulate research to supply more precise and effective cancer immune checkpoint therapies for a large number of tumors.

A growing amount of evidence suggests that ubiquitination and deubiquitination of PD-1/PD-L1 play crucial roles in the regulation of PD-1 and PD-L1 protein stabilization and dynamics. PD-1/PD-L1 is a major coinhibitory checkpoint pathway that modulates immune escape in cancer patients, and its engagement and inhibition has significantly reshaped the landscape of tumor clearance. The abnormal ubiquitination and deubiquitination of PD-1/PD-L1 influence PD-1/PD-L1-mediated immunosuppression. In this review, we describe the ubiquitination- and deubiquitination-mediated modulation of PD-1/PD-L1 signaling through a variety of E3 ligases and deubiquitination enzymes (DUBs). Moreover, we briefly expound on the anticancer potential of some agents that target related E3 ligases, which further modulate the ubiquitination of PD-1/PD-L1 in cancers. Therefore, this review reveals the development of a highly promising therapeutic approach for cancer immunotherapy by targeting PD-1/PD-L1 ubiquitination.

The Anaphase Promoting Complex (APC) has been characterized to play pivotal roles in regulating the timely cell cycle progression by forming two functionally distinct E3 ubiquitin ligase sub-complexes, APC^Cdc20 and APC^Cdh1. Interestingly, recent studies have shown that Cdh1 is functioning as a tumor suppressor whereas Cdc20 may function as an oncoprotein to promote the development and progression of human cancers. In this review, we will discuss the physiological role of Cdc20 and its downstream substrates in vitro and in the transgenic mouse model reminiscent of the pathogenesis of human cancers. Furthermore, we summarize recent findings to indicate that Cdc20 may represent a promising therapeutic target, thus development of Cdc20 inhibitors could be useful for achieving better treatment outcome of cancer patients.