Immunometabolic Interactions in Obesity: Implications for Therapeutic Strategies

Obesity is characterized by excessive fat accumulation that triggers chronic low-grade inflammation and systemic immune dysregulation, significantly increasing the risk of metabolic disorders including insulin resistance, type 2 diabetes, and cardiovascular disease. This review examines the bidirectional relationship between obesity and immune dysfunction, focusing on how immune cell infiltration in adipose tissue drives inflammatory processes. We highlight the phenotypic shifts in key immune populations-macrophages polarized toward proinflammatory M1 phenotypes, T cell exhaustion occurrs, and alterations appear in B cells, natural killer (NK) cells, and dendritic cells-that collectively contribute to metabolic deterioration. The gut microbiome emerged as a critical mediator in this relationship, influencing both immune responses and metabolic regulation through gut-liver and gut-brain axes. We explore emerging immunomodulatory therapeutic strategies, including anti-inflammatory agents, microbiota interventions, and targeted immune therapies such as innovative nanomedicine approaches. The review also addresses the challenges of immunotherapy in obesity, particularly the paradoxical effects observed in cancer immunotherapy outcomes and the need for personalized treatment approaches. Artificial intelligence is highlighted as a potential tool to enhance patient stratification and treatment optimization in future immunomodulatory interventions. Understanding these immunometabolic interactions provides a foundation for developing more effective therapeutic strategies that could transform obesity management and reduce the burden of obesity-related metabolic diseases.