Leptin Signaling at the Crossroads of Obesity, Immunity, and Cancer: Mechanistic Insights and Therapeutic Implications

Leptin, an adipokine predominantly secreted by adipose tissue, has exhibited a wide range of biological functions, including regulation of energy balance, appetite, and metabolism. Accumulating evidence has demonstrated that leptin also plays a role in obesity-associated tumor progression. Elevated circulating leptin levels in obese individuals, together with the close association between obesity and increased cancer risk, have led to growing interest in leptin as a potential mediator linking adiposity to tumor growth and immune dysregulation. Recent studies have shown that leptin can directly interact with immune cells within the tumor microenvironment and promote dysfunction or exhaustion in various immune cell populations, thereby impairing anti-tumor immunity. These findings suggest that tumor-promoting effects of leptin may be mediated, at least in part, through modulation of anti-tumor immune responses. Notably, metabolic reprogramming of both immune cells and cancer cells appears to be a critical mechanism underlying leptin-mediated tumor progression and immune dysfunction. Since obesity is characterized by altered adipokine production, chronic low-grade inflammation, and immune dysregulation, leptin may serve as a critical mediator linking excess adiposity to impaired immune surveillance and cancer progression. However, the biological effects of leptin are highly context-dependent. Although leptin predominantly supports tumor progression and immune suppression in many obesity-associated cancers, it may also exert immune-stimulatory or anti-tumor effects under specific conditions. This review summarizes current mechanistic insights into the role of leptin in tumor progression and immune regulation. We also highlight therapeutic strategies that integrate leptin-targeted approaches with immunotherapy.