A strategic review of STAT3 signaling inhibition by phytochemicals for cancer prevention and treatment: Advances and insights

Cancer remains a significant global health concern. The dysregulation of signaling networks in tumor cells greatly affects their functions. This review intends to explore phytochemicals possessing potent anticancer properties that specifically target the STAT3 signaling pathway, elucidating strategies and emphasizing their potential as promising candidates for cancer therapy. The review comprehensively examines various STAT3 inhibitors designed to disrupt the signaling cascade, including those targeting upstream activation, SH2 domain phosphorylation, DNA binding domain (DBD), N-terminal domain (NTD), nuclear translocation, and enhancing endogenous STAT3 negative regulators. A literature review was conducted to identify phytochemicals with anticancer activity targeting the STAT3 signaling pathway. Popular research databases such as Google Scholar, PubMed, Science Direct, Scopus, Web of Science, and ResearchGate were searched from the years 1989 - 2023 based on the keywords “Cancer”, “STAT3”, “Phytochemicals”, “Phytochemicals targeting STAT3 signaling”, “upstream activation of STAT3”, “SH2 domain of STAT3”, “DBD of STAT3”, “NTD of STAT3, “endogenous negative regulators of STAT3”, or “nuclear translocation of STAT3”, and their combinations. A total of 264 relevant studies were selected and analyzed based on the mechanisms of action and the efficacy of the phytocompounds. The majority of the discussed phytochemicals primarily focus on inhibiting upstream activation of STAT3. Additionally, flavonoid and terpenoid compounds exhibit multifaceted effects by targeting one or more checkpoints within the STAT3 pathway. Analysis reveals that phytochemicals targeting upstream activation predominantly belong to the classes of flavonoids and terpenoids, which hold significant promise as effective anticancer therapeutics. Future research in this field can be directed towards exploring and developing these scrutinized classes of phytochemicals to achieve desired therapeutic outcomes in cancer treatment.