Itaconate in cancer immunity: Evidence, ambiguities, and translational barriers

Itaconate (ITA) is an endogenous metabolite produced from cis-aconitate by the immune-responsive gene 1-encoded enzyme aconitate decarboxylase 1 and has emerged as an important immune-metabolic regulator in cancer. In the tumor immune microenvironment, endogenous ITA is increasingly associated with an immunosuppressive microenvironment, tumor cell immune evasion, and therapeutic resistance, supporting a predominantly pro-tumor role in vivo. Nevertheless, the field remains clouded by several unresolved issues, including the heavy reliance on a limited number of tumor models, the persistent conflation of endogenous ITA with membrane-permeable derivatives, the incomplete definition of the mechanisms underlying its intercellular effects, and the uncertain cross-species relevance of current findings. Here, we highlight recent evidence supporting the physiological functions of endogenous ITA in cancer, delineate major boundaries and ambiguities in current interpretation, and outline key questions that should guide future mechanistic and translational studies.