ACE Does More Than Regulate Blood Pressure — It Supercharges Immune Cells Against Cancer and Infection

ACE (angiotensin-converting enzyme) has a second, nonclassical function beyond making angiotensin II: when immune cells like macrophages and neutrophils increase their ACE expression, it dramatically boosts their ability to fight tumors, infections, atherosclerosis, and Alzheimer's disease. Genetically modified 'ACE 10/10' mice with increased macrophage ACE were much more resistant to all these conditions. This immune-boosting effect works through an unknown peptide (not angiotensin II) that shifts macrophage metabolism toward increased mitochondrial fat burning and ATP production. Conversely, ACE inhibitor drugs reduce neutrophil bacteria-killing ability in both mice and humans.

This is a review article summarizing the authors' extensive research program on nonclassical ACE functions. It draws on data from genetically modified mouse models (ACE 10/10 mice with enhanced macrophage ACE, and NeuACE mice with enhanced neutrophil ACE), metabolic profiling, and studies of ACE inhibitor effects on immune function in mice and humans.

ACE inhibitors are among the most prescribed drugs worldwide for blood pressure. This review reveals that ACE does far more than regulate blood pressure — it produces an unidentified peptide that supercharges immune cell function. This has profound implications: ACE inhibitors may inadvertently weaken immune responses, and identifying the mystery peptide could create new treatments for cancer, infections, atherosclerosis, and Alzheimer's disease.

ACE inhibitors are taken by hundreds of millions of people. If these drugs weaken immune function, even modestly, the public health implications are enormous. Conversely, if the mystery peptide produced by ACE can be identified and synthesized, it could become a new class of immune-boosting therapy for cancer, chronic infections, and neurodegenerative diseases. This is a rare example where a well-studied enzyme turns out to have a completely hidden function.

Most evidence comes from genetically modified mouse models. The unknown peptide responsible for the immune effects has not been identified or purified. The clinical significance of ACE inhibitor-induced immune suppression in humans needs further study. The review is largely from one research group's body of work.