Holding cancer in line: the role of the electron transport chain in tumor-associated macrophages

Tumor-associated macrophages (TAMs) are a highly heterogeneous population of innate immune cells that is widely enriched in the tumor microenvironment (TME). By suppressing anti-cancer immunity, TAMs sustain tumor growth, metastasis development and contribute to therapy resistance. Due to their remarkable plasticity, TAMs can be reprogrammed towards immune-stimulatory phenotypes, representing a compelling therapeutic option. The mitochondrial electron transport chain (ETC) is central in fueling macrophage metabolism by coupling electron flow with proton transfer to produce Adenosine Triphosphate (ATP). During inflammation, remodeling of the ETC has been shown to regulate macrophage polarization and cytokine production. However, how ETC perturbations influence macrophage phenotypes in other diseases, as during cancer progression and within a nutrient-restricted environment remains largely unexplored. In this mini-review, we examine the role of the ETC and its individual respiratory complexes in governing tumor-associated macrophage behavior, their involvement in tumor immunity, and we discuss the potential to exploit this axis for innovative immunotherapeutic strategies, while also considering current challenges and limitations.