Phytochemicals Alleviate Tumorigenesis by Regulation of M1/M2 Polarization: A Systematic Review of the Current Evidence

ABSTRACT Cancers are increasingly common and significantly impact patients' quality of life and longevity. The role of macrophages in tumorigenesis is critical, and natural compounds have long been recognized as valuable sources of bioactive agents for treating this condition. However, no systematic review has been performed on the role of phytochemicals impacting tumorigenesis by M1/M2 macrophage polarization. The aim of this study is to systematically review phytochemicals that relieve tumorigenesis by impacting M1/M2 macrophage polarization and investigate related signaling pathways. This systematic review adheres to PRISMA 2020 guidelines and statements. Scientific databases, MEDLINE, Scopus, and Web of Science, have been searched from inception to October 2023. This review includes English original articles on the role of phytochemicals, whole plant extracts, and polyherbal formulas in ameliorating tumorigenesis through M1/M2 polarization while excluding non‐English articles, non‐original research, and unrelated studies according to title, abstract, and full‐text screening. Shreds of evidence were gathered from cellular and animal studies about the beneficial impacts of phytochemicals against tumorigenesis by impacting M1/M2 macrophage polarization. Critical assessment of in vitro and in vivo studies was performed by the CRIS and ARRIVE guidelines. Due to the high level of heterogeneity of the collected data, only a narrative synthesis was performed. Of 741 collected articles, only 35 remained. Polyphenols are the most highlighted group. Phytochemicals affect cytokines related to M1, such as CD80, CD86, CD64, and iNOS, and M2, like CXCR‐1, CXCR‐2, and TGF‐β, in various cancer models. Together, these compounds exerted protective effects against tumorigenesis in preclinical cancer models. Furthermore, high‐quality clinical experiments are recommended to cover the limitations of the current study, which are reliance on preclinical evidence, lack of clinical trials, and exclusion of non‐English and grey literature.