Plant-derived immunomodulators in cancer: Balancing immune activation and suppression within the tumor microenvironment

The immune system is central to the prevention and control of cancer, yet tumors evolve multiple strategies to subvert immune surveillance. Checkpoint inhibitors targeting CTLA-4, PD-1, and PD-L1 have revolutionized oncology by demonstrating that therapeutic restoration of T cell activity can yield durable remissions. However, their efficacy remains limited by the profoundly immunosuppressive tumor microenvironment (TME), where regulatory immune cells, suppressive cytokines, and metabolic stressors converge to dampen effector function. As interest in integrative and complementary approaches grows, plant-derived compounds - long used in traditional medicine - have been identified as bioactive agents capable of modulating immune function. This review focuses on three key phytochemicals: piperlongumine, berberine, and epigallocatechin gallate (EGCG). Piperlongumine, a pro-oxidative alkaloid from Piper longum, suppresses T cell activation and promotes regulatory T cell differentiation, suggesting potential for chronic inflammation but raising caution in oncology. Berberine, an isoquinoline alkaloid from Berberis vulgaris, reduces PD-L1 expression via CSN5 inhibition, thereby mimicking checkpoint blockade and enhancing cytotoxic T cell activity in preclinical models. EGCG, the major polyphenol in green tea, downregulates PD-L1 expression and augments anti-tumor immunity in murine melanoma. We critically assess the promise and pitfalls of these compounds in cancer immunotherapy, emphasizing mechanistic insights, pharmacokinetics, translational hurdles, and potential risks of interfering with established therapies. A precision immunology framework - integrating immune monitoring, patient stratification, and controlled clinical trials - will be essential to determine whether phytochemicals can be safely and effectively incorporated into oncology. Far from being benign, plant-derived agents exert potent immune effects that could either complement or compromise modern immunotherapy, underscoring the need for rigorous evaluation.