Obesity-induced metabolic reprogramming of the tumor immune microenvironment: mechanisms, spatial niches, and immunotherapy response

Abstract

Obesity is a major global health challenge and an established risk factor for cancer. Beyond increasing tumor incidence, obesity reshapes the tumor immune microenvironment (TIME) through systemic metabolic reprogramming, adipokine dysregulation, chronic inflammation, and gut microbiota alterations. These systemic changes create spatially organized immunosuppressive metabolic niches, including adipocyte-rich, hypoxic/lactate-enriched, myeloid-dense, and CAF/ECM barrier regions. Such niches restrict effector T-cell and NK-cell function while supporting regulatory T cells, tumor-associated macrophages (TAMs), and myeloid-derived suppressor cells (MDSCs), collectively promoting tumor progression and therapy resistance. Obesity also generates context-dependent effects on immune checkpoint blockade (ICB), a phenomenon known as the “obesity paradox, ” in which immune suppression coexists with increased checkpoint dependency. Understanding how obesity modulates tumor cell metabolism, immune-cell metabolic fitness, and stromal remodeling is essential for designing effective interventions. Therapeutic strategies combining metabolic modulation, ICB, lifestyle intervention, and microbiota-targeted therapies may convert obesity-driven immune suppression into actionable vulnerabilities. Integrating systemic metabolic indicators, immune-cell signatures, and spatial biomarkers will enable precision stratification of patients and inform combination immunotherapy strategies in obesity-associated cancers.