Trained immunity modulators: A new frontier in immunoregulation and disease intervention

Immunotherapy has emerged as one of the most revolutionary approaches in disease treatments. However, most current and emerging immunotherapeutic strategies primarily target the adaptive immune system. Recent studies have elucidated that innate immune myeloid cells can develop sustained phenotypic modifications upon exposure to specific immunomodulators, mediated through coordinated metabolic alterations and epigenetic reprogramming. These changes lead to either hyperresponsive or hyporesponsive innate immune cells when exposed to secondary stimuli, a phenomenon termed "trained immunity". Over the past decade, trained immunity has garnered increasing attention for its potential to enhance host defense. While numerous studies have investigated trained immunity modulators, comprehensive reviews-especially those focusing on recently identified modulators-are still lacking. This review aims to elucidate the molecular mechanisms underlying trained immunity and its dual roles in various pathological conditions. We provide a comprehensive summary of the classifications and mechanisms of trained immunity inducers and suppressors identified in the past decade, emphasizing their therapeutic potential in immune-related diseases. Additionally, we discuss the limitations of these trained immunity modulators and offer insights into future directions for developing novel therapies targeting trained immunity. Key scientific concepts of review: This review first provide an overview of the molecular mechanisms underlying trained immunity, highlighting both its beneficial and detrimental effects on various diseases. Then it focuses on summarizing the classification and mechanisms of trained immunity modulators, including vaccines, polysaccharides, nanobiologics, endogenous mediators and other non-canonical modulators. Finally, the limitations of current trained immunity modulators and insights into future directions for developing novel therapies targeting trained immunity are proposed.