Beyond a covariate: sex as a mechanistic determinant of Immunometabolism

In the past two decades, two major conceptual advances that have shaped the modern immunological field are the establishment of immunometabolism as a discipline and the growing understanding of how immune systems can drastically differ based on sex. Considering the well-known wide-ranging impact of sex on metabolic processes, these innovations would potentially be expected to be intricately linked. However, the majority of immunometabolism studies do not consider sex, or treat sex as a covariate that should be statistically adjusted for. Therefore, most studies interrogating how metabolic processes impact immune cell function may conceal how these processes are fundamentally different in males and females, and how they may shift in response to changing sex hormone levels across the lifespan. In this perspective, we argue that sex should be treated as a fundamental mechanistic input in immunometabolism, rather than solely as a statistical confounder or covariate, with direct consequences for how existing and new data are interpreted, and for how new therapies for immunometabolic health conditions are developed.