Simple SummaryTumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) plays an important role in apoptosis and tumor immunosurveillance. Because TRAIL selectively induces apoptosis in tumor cells, there is growing interest in using it as a cancer therapy agent, but the development of TRAIL resistance has limited its clinical development. Recent evidence suggests that the TRAIL pathway can activate the immunological checkpoint protein programmed death-ligand 1 (PD-L1), which has recently been found to play an important role in TRAIL resistance and tumor invasion. Thus, targeting PD-L1 could be a promising new therapeutic strategy to improve TRAIL-based treatments in human cancers.AbstractTumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a member of the TNF superfamily that selectively induces apoptosis in tumor cells without harming normal cells, making it an attractive agent for cancer therapy. TRAIL induces apoptosis by binding to and activating its death receptors DR4 and DR5. Several TRAIL-based treatments have been developed, including recombinant forms of TRAIL and its death receptor agonist antibodies, but the efficacy of TRAIL-based therapies in clinical trials is modest. In addition to inducing cancer cell apoptosis, TRAIL is expressed in immune cells and plays a critical role in tumor surveillance. Emerging evidence indicates that the TRAIL pathway may interact with immune checkpoint proteins, including programmed death-ligand 1 (PD-L1), to modulate PD-L1-based tumor immunotherapies. Therefore, understanding the interaction between TRAIL and the immune checkpoint PD-L1 will lead to the development of new strategies to improve TRAIL- and PD-L1-based therapies. This review discusses recent findings on TRAIL-based therapy, resistance, and its involvement in tumor immunosurveillance.