Innate immune memory: The evolving role of macrophages in therapy

Trained immunity is reshaping our understanding of host defense by demonstrating that innate immune cells once thought to lack memory can be reprogrammed to mount heightened responses to subsequent challenges. Unlike tolerance, differentiation, or priming, trained immunity relies on epigenetic and metabolic rewiring of resident myeloid cells, particularly in mucosal barriers such as the skin, gut, and lungs, where these cells provide continuous protection against toxins and pathogens. Here, we review recent advances showing how an initial stimulus endows monocytes and macrophages with long-lasting functional changes that can be either protective or maladaptive upon re-exposure. We highlight therapeutic opportunities that harness trained immunity to boost vaccine efficacy and discuss strategies to modulate this program in cancer and hyper-inflammatory disorders. Finally, we propose new directions for enhancing or dampening trained immunity to promote human health.