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PD-L1, frequently expressed in human cancers, engages with PD-1 on immune cells and contributes to cancer immune evasion. As such, antibodies blocking the PD-1/PD-L1 interaction reactivate cytotoxic T cells to eradicate cancer cells. However, a majority of cancer patients fail to respond to PD-1/PD-L1 blockade with unclear underlying mechanism(s). Recent studies revealed that PD-L1 expression levels on tumor cells might affect the clinical response to anti-PD-1/PD-L1 therapies. Hence, understanding molecular mechanisms for controlling PD-L1 expression will be important to improve the clinical response rate and efficacy of PD-1/PD-L1 blockade. In this review, we primarily focus on summarizing PD-L1 regulation and its potential roles in regulating antitumor immune response, with purpose to optimize anti-PD-1/PD-L1 therapies, benefiting a wider cancer patient population. Highlights PD-1/PD-L1 immune checkpoint blockade exhibits promising efficacy for human cancer treatment. However, only limited cancer patients (15%–25%) respond to anti-PD-1/PD-L1 immunotherapy. Exploring resistance mechanisms will therefore enhance patient selection, response rate, and efficacy for anti-PD-1/PD-L1 treatment to benefit more cancer patients. Recent studies demonstrated that PD-L1 expression levels on tumor cells might correlate with the response rate and efficacy of PD-1/PD-L1 blockade. Hence, understanding the molecular mechanisms for regulating PD-L1 abundance will offer more strategies to improve PD-1/PD-L1 blockade in cancer therapy. Increasing evidence reveals that PD-L1 is regulated via various mechanisms, including genomic alterations, epigenetic modifiers, transcriptional regulation, microRNAs, post-translational modification, and DNA damage signaling, as well as PD-L1 interacting protein(s) to modulate immunosuppression in cancer patients. [ABSTRACT FROM AUTHOR]