Immunomodulatory and anticancer effects of phytochemicals: A comprehensive analysis

Natural compounds have been a part of traditional medicine for generations, and recent studies are now recognizing their potential to influence the immune system in cancer treatment. This review focuses on how specific plant-derived chemicals can modulate immune checkpoints such as PD-1, PD-L1, and CTLA-4, which play a central role in cancer immunotherapy, mainly in preclinical and early translational studies. Compounds including curcumin, isothiocyanates, apigenin, luteolin, and berberine demonstrate mechanisms that inhibit immune evasion, are associated with enhanced cytotoxic T-cell responses, and modulate the tumor microenvironment, primarily in the in vitro and in vivo models. Several other phytochemicals such as anthocyanins, triptolide, and epigallocatechin gallate, have shown promise in preclinical models by disrupting oncogenic signaling pathways and promoting antitumor immunity. Although many of these agents face challenges such as low bioavailability, advances in drug delivery systems, and synergistic combinations with current therapies offer a compelling direction for potential cancer treatments. Understanding the molecular interactions of these natural agents can provide hypothesis generation and novel insights into potential effective and less toxic immunotherapeutic approaches. This comprehensive review further provides a thorough understanding of phytochemicals' translational and mechanistic relevance, highlights knowledge gaps, and guides future research directions that could improve integrative cancer immunotherapy techniques, noting that most of the available evidences are derived from preclinical studies. SIGNIFICANCE STATEMENT: Accumulating evidence suggests that phytochemicals modulate immune responses within the tumor microenvironment. These compounds have diverse mechanisms, ranging from cytokine modulation to effects on macrophages, T-cells, and pathways such as STAT3, NF-κB, and PD-L1. This review clarifies how phytochemicals influence immunotherapy outcomes and how they might be used more deliberately in cancer care. Unlike prior reviews, this work explicitly classifies phytochemicals according to whether they enhance antitumor immunity, suppress immune activation, or exert context-dependent dual effects relevant to immune checkpoint therapy.