Focus on immune checkpoint PD-1/PD-L1 pathway: New advances of polyphenol phytochemicals in tumor immunotherapy

The rise of cancer immunotherapy, particularly the use of immune checkpoint inhibitors (ICIs), has significantly changed the clinical treatment paradigm for patients with cancer. The programmed death ligand 1 (PD-L1) protein in the tumor microenvironment (TME) binds to programmed cell death protein 1 (PD-1) on the surface of T cells and initiates the PD-1 / PD-L1 immunosuppressive program, which is currently one of the most promising target pathways for immunotherapy. However, problems such as low response rates, single targets, and high immunotoxicity have limited their clinical application. The upregulation or downregulation of PD-L1 expression in the TME can enhance the therapeutic efficacy of anti-PD-(L)1 inhibitors, and their combination with immunotherapy drugs may represent a novel anti-cancer treatment approach. The diverse immunomodulatory potential of polyphenolic compounds of plant origin offers a new direction for tumor immunotherapy. This review summarizes recent advances in research investigating the PD-L1 modulatory function of polyphenolic compounds and their combination with anti-PD-1/PD-L1 immunotherapy. In addition, we provide new insights into the advantages of polyphenolic compounds in macroscopic regulation in the tumor microenvironment and deeply explore the clinical application prospects and challenges of their immunotherapeutic potential. This study covers the most comprehensive understanding to date of polyphenolic compounds interfering with the PD-1/PD-L1 pathway in TME, intending to provide a comprehensive and valuable source of information regarding the development of polyphenolic phytochemicals as combinatorial adjuvant candidates for experimental studies, clinical applications, and their synergy with immune checkpoint blockade therapy.