The obesity–neuroinflammation–cancer axis: neuroimmune remodeling and therapeutic opportunities

Abstract

Obesity is a chronic metabolic and inflammatory disorder associated with increased risk and poorer outcomes in multiple malignancies. Although adipose inflammation, insulin resistance, and altered adipokine signaling are established links between obesity and cancer, these mechanisms do not fully explain how systemic metabolic stress is translated into persistent changes in tissue immunity and tumor behavior. This narrative Review proposes the obesity–neuroinflammation–cancer axis as an integrative framework in which obesity-associated metabolic and inflammatory signals perturb central and peripheral neural homeostasis, while neuroinflammation, neural remodeling, and neuroendocrine signaling reshape the tumor microenvironment through reciprocal interactions among nerves, immune cells, stromal cells, and cancer cells. We focus on obesity-induced neuroinflammation, tumor neuroimmune remodeling, and neuroimmunometabolic feedback, highlighting sympathetic signaling, leptin–JAK/STAT3, NF-κB, inflammasome pathways, and metabolic reprogramming. We further evaluate therapeutic opportunities involving metabolic, inflammatory, and adrenergic interventions, including their combination with immune checkpoint blockade, while emphasizing inconsistent clinical evidence and the need for composite biomarkers. This framework is intended as a testable synthesis rather than a universally established causal pathway and identifies cancer-type-specific neuroimmune circuits as a priority for future translational research.