What do we really know about human immunometabolism in inflammatory disease?

Cellular metabolism is now recognised as an active regulator of immune cell activation, differentiation, and function. However, much of this conceptual framework derives from in vitro systems and animal models that may not fully reproduce human physiology or disease. Many studies of human immune metabolism are constrained by artificial culture conditions, tissue dissociation, limited pathway coverage, and a reliance on static measurements that do not directly quantify metabolic flux in vivo. Interpretation is further complicated by the use of blood samples as a surrogate for diseases that arise in specialised tissues, such as synovium, gut, and skin, and by the influence of systemic physiology, including hepatic substrate regulation, adipose tissue, endocrine and neuronal signalling, and the gut microbiota. In this review, we examine what current experimental approaches can infer about immune metabolism in humans, with a focus on immune-mediated inflammatory diseases. Oncology provides a valuable methodological precedent through its use of tissue sampling, spatial profiling, and stable isotope tracing, while also illustrating the challenges of assigning metabolic activity to individual cell populations within heterogeneous tissues. We propose five priorities for the field: move beyond blood to inflammatory tissue; complement static abundance with dynamic, stable isotope flux analysis; integrate single cell, spatial, and imaging modalities; incorporate carefully designed human metabolic perturbations; and account for the wider systemic and pre-analytical context. The next phase of human immunometabolism should move from pathway annotation in reductionist models towards dynamic, tissue-resolved, and clinically anchored studies of immune cell metabolism in vivo.