Reprogramming the immunologically cold landscape of prostate cancer through MAOA inhibition

Prostate cancer (PC) is notoriously known for exhibiting an immunologically cold phenotype in the tumor immune microenvironment (TIME), leading to the need for interventions to enhance immunotherapy efficacy. Recent findings by Zhao et al. in the Journal for ImmunoTherapy of Cancer identified stromal monoamine oxidase A (MAOA), a key enzyme that degrades monoamine neurotransmitters and plays a role in the neuroendocrine system, as a critical regulator of the immune response to PC. Altering MAOA levels in myofibroblastic cancer-associated fibroblasts, either genetically or pharmacologically, can reprogram PC's TIME to modulate CD8⁺ T cell-mediated cytotoxicity through the WNT5A-Ca²⁺-NFATC1 signaling axis, highlighting the stromal influences on CD8⁺ T cell cytotoxic activity within the TIME. The inactivation of MAOA synergizes with immune checkpoint blockade therapies to reverse the trajectory of prostate tumor growth. This work offers a promising therapeutic avenue for PC by positioning MAOA as a stromal modulator of immune response as well as a target for combination immunotherapies. The current commentary aims to present our perspective on how a metabolic enzyme can change the immune landscape of the tumor microenvironment, what we have learned, and what we can develop in the future.