ABSTRACT Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape of malignant tumors; however, their clinical efficacy remains constrained by primary or acquired resistance and immune‐related adverse events (irAEs). To improve the overall efficacy of immunotherapy, the development of synergistic strategies with high efficacy and low toxicity has emerged as a critical research direction. Natural products, characterized by their multi‐target properties and low toxicity, exhibit unique advantages in enhancing immunotherapy responses and represent promising immunotherapeutic adjuvants. This review systematically delineates the underlying mechanisms of ICI resistance and immune‐related adverse events. It further provides a comprehensive summary of the currently elucidated mechanisms by which natural products function as immunotherapeutic adjuvants, focusing on three interconnected dimensions of synergistic enhancement: enhancing T cell function through epigenetic and metabolic reprogramming to reverse T cell exhaustion and promote memory T cell generation; remodeling the immune microenvironment by inducing immunogenic cell death and regulating immunosuppressive cells; and modulating the gut microbiota‐immune axis to remotely activate systemic anti‐tumor immunity through gut microbiota and their metabolites. The three aspects are interdependent and form a synergistic regulatory network. This review aims to provide a theoretical basis and strategic reference for the development and application of natural products in combination immunotherapy.
Liu et al. (Mon,) studied this question.