Plant-derived Phytochemicals as Modulators of the Tumor Immune Microenvironment: Emerging Roles in Cancer Immunotherapy

Abstract

Background: The tumour immune microenvironment (TIME) is a dynamic immunosuppressive network of cellular and molecular mediators that promotes immune evasion and limits the efficacy of current immunotherapeutic strategies. Aim: This review critically evaluates plant-derived phytochemicals as multi-target modulators of the TIME, with a mechanistic and translational focus on their roles in cancer immunotherapy. Methodology: A narrative synthesis of primary research and systematic reviews published between January 2015 and June 2026 was conducted using PubMed/MEDLINE, Scopus, Web of Science, ClinicalTrials.gov, and the Cochrane Library, with an emphasis on mechanistic precision and clinical relevance. Results: Phytochemical classes including polyphenols (curcumin, resveratrol, EGCG), flavonoids (quercetin, luteolin), alkaloids (berberine), terpenoids (artemisinin), and organosulfur compounds (sulforaphane) exert pleiotropic immunomodulatory effects. These include repolarization of tumour-associated macrophages from the M2 to the M1 phenotype, suppression of regulatory T cells and myeloid-derived suppressor cells, restoration of cytotoxic T lymphocyte function, augmentation of dendritic cell maturation, downregulation of immune checkpoint molecules (PD-L1, PD-1, CTLA-4), and induction of immunogenic cell death through pyroptotic and ferroptotic pathways. Crucially, several agents demonstrate preclinical synergy with immune checkpoint inhibitors, converting immunologically 'cold' tumours into 'hot' ones. However, clinical translation is constrained by poor bioavailability, pharmacokinetic variability and the absence of randomised trial data. Conclusions: Phytochemicals represent scientifically compelling but clinically underexploited immunomodulatory agents. Their rational integration into precision immuno-oncology may expand the therapeutic frontier of cancer immunotherapy.