Immune checkpoints and immunoregulation in metabolic diseases and cancers: pathological mechanisms and therapeutic potential

Abstract

The global prevalence of metabolic diseases, notably obesity, diabetes mellitus, and thyroid disorders, has risen dramatically in recent decades, posing a significant threat to public health. While conventional pharmacological interventions remain the cornerstone of management, they face considerable limitations, including adverse effects and the development of drug resistance, underscoring the urgent need for alternative therapeutic strategies. Intriguingly, immune checkpoint molecules, originally recognized for their transformative role in cancer immunotherapy, are now gaining attention as pivotal regulators of metabolic homeostasis. Growing research demonstrates that immune checkpoint pathways, particularly the PD-1/PD-L1 axis, play dual roles in immune regulation and metabolic modulation by orchestrating inflammatory responses and energy metabolism. For instance, in obesity, PD-1/PD-L1 signaling promotes the polarization of adipose tissue macrophages from a proinflammatory M1 phenotype toward an anti-inflammatory M2 state, thereby mitigating chronic low-grade inflammation and associated metabolic dysfunction. These findings highlight the potential of immune checkpoint modulation as a novel therapeutic strategy for metabolic disorders. However, despite these advances, the role of immune checkpoints in metabolic diseases remains underexplored, with limited comprehensive reviews on the subject. This review comprehensively elucidates the pathophysiological mechanisms and translational potential of immune checkpoint regulation in obesity, diabetes, and thyroid disease while proposing novel directions for clinical intervention.