Enhancing NK Cell Antitumor Activity With Natural Compounds: Research Advances and Molecular Mechanisms

In recent years, immunotherapy has become a novel antitumor strategy in addition to traditional surgery, radiotherapy, and chemotherapy and has exhibited promising results in clinical applications. Despite significant breakthroughs in immunotherapy, such as immune checkpoint blockade and CAR-T cell therapy, it remains necessary to develop more efficacious, safer, and cheaper immunotherapeutic drugs due to factors including small reaction populations, acquired resistance, adverse side effects, and high costs. Natural killer (NK) cells are preeminent cytotoxic lymphocytes of the innate immune system that act as the first line of defense against tumors and synergistically enhance the adaptive immune response of T lymphocytes. Therefore, boosting the antitumor function of NK cells is an important direction in the development of immunotherapy. For decades, various immunotherapies such as adoptive cell therapy, antibody drugs, cytokines supplement, and chemical immunomodulators have been developing rapidly to improve the function of NK cells. Compared to biological immunotherapy, immunomodulators derived from natural products have outstanding advantages of low immunogenicity, multi-targeting, and cost-effectiveness. Currently, increasing attention is being focused on discovering NK cell-stimulating agents from natural products, such as polysaccharides, alkaloids, terpenoids, saponins, phenolics, and quinones. This review aims to categorize and summarize the comprehensive research progress on these natural products, discuss their potential molecular mechanisms in regulating NK cells, and explore their clinical applications as standalone treatments or in combination with conventional chemotherapy regimens.