Narrative review advocates multi-omics models to clarify exercise associationsExercise links to health benefits, but direct causation remains associative

The concept of “trained immunity,” which refers to a type of long-term immunological memory within innate cells, has significantly challenged the traditional division between the non-specific innate and antigen-specific adaptive immune systems. Simultaneously, it is now understood that the resolution of inflammation is not just a passive return to homeostasis but rather an active, strictly regulated biological process. This comprehensive review synthesizes these evolving concepts by hypothesizing that exercise, through its pleiotropic effects on cellular metabolism, may strongly stimulate both the active resolution of inflammation and the formation of innate immunological memory via epigenetic control (emerging evidence from non-exercise models like Bacillus Calmette-Guérin (BCG) vaccination and β-glucan exposure suggests parallels, but direct causation in exercise remains associative). The review describes the biological foundations of this relationship, including the metabolic changes that define trained immunity and the epigenetic reprogramming of myeloid progenitors. It explores the central role of myokines, particularly Interleukin-6 (IL-6), which act as critical mediators, steering the immune response toward a pro-resolving phenotype, while acknowledging contributions from other factors such as IL-15, catecholamines, and neural signals. Furthermore, the review outlines how exercise promotes the synthesis of specialized pro-resolving mediators (SPMs) and enhances efferocytosis, a key cellular mechanism for restoring tissue homeostasis. By providing a unifying framework, this analysis offers a mechanistic explanation for the profound health benefits of exercise, from enhanced immunosurveillance to the prevention of chronic inflammatory diseases. The review concludes by highlighting significant knowledge gaps and advocating for the use of multi-omics and in vivo models to fully elucidate this complex nexus and translate these discoveries into novel therapeutic strategies.