Immunotherapy has transformed oncology by reactivating anti-tumour immunity, yet analogous strategies to restore immune regulation in chronic inflammatory diseases remain underdeveloped. Cardiovascular disease - the leading cause of mortality worldwide - is driven not only by lipid accumulation but by persistent, unresolved vascular inflammation. Despite lipid lowering and systemic anti-inflammatory therapy, residual inflammatory risk remains high, highlighting a critical unmet need for immune-directed therapies that rebalance, rather than suppress, immune responses.
Myeloid-derived suppressor cells (MDSCs) are potent regulators of T cell activation and immune homeostasis. While extensively studied as pathological suppressors in cancer, their role in chronic vascular inflammation is poorly defined. We hypothesised that impaired suppressor potency, rather than immune hyperactivation alone, contributes to persistent vascular inflammation and that restoring endogenous regulatory pathways may represent a tractable immunomodulatory strategy.
Using experimental models of atherosclerosis, we identify tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) as a regulator of MDSC function. TRAIL deletion alters MDSC distribution across blood, lymphoid tissues and the aorta, and reduces their capacity to suppress T cell proliferation. This functional impairment is associated with dysregulation of nitric oxide- and reactive oxygen-dependent effector pathways that underpin suppressor activity. In human vascular disease, circulating and plaque-associated TRAIL expression is reduced in patients with advanced pathology. Single-cell and flow cytometric analyses confirm the presence of MDSC-like populations within human atherosclerotic lesions, where they demonstrate suppressive capacity ex vivo.
Targeted activation of TRAIL receptors using agonistic antibodies enhances the immunosuppressive function of human MDSCs, restoring their ability to restrain T cell proliferation. Together, these findings provide proof-of-concept that endogenous immune regulatory circuits can be therapeutically modulated in chronic vascular inflammation. Collectively, this work defines restoration of immune regulatory balance as a rational immunotherapy direction for cardiovascular disease.