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Review
Obesity-associated metabolic and immune dysregulation: the double-edged sword in cancer immunotherapy outcomes
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Abstract:
[Abstract] Obesity is a risk factor for various malignant tumors and is often associated with poor prognosis. However, in certain tumors such as melanoma (MM) and non-small cell lung cancer (NSCLC), obese patients exhibit better survival benefits from immunotherapy than normal-weight patients, a phenomenon known as the "obesity paradox," whose underlying mechanisms may be closely related to obesity-associated immune dysregulation. Recent studies have shown that obesity not only induces systemic immune dysregulation through adipokine imbalance and chronic inflammation but also directly impairs the functions of CD8+ T cells, natural killer (NK) cells, and dendritic cells (DCs) in the tumor microenvironment (TME) through metabolic reprogramming (e.g., lipid overload, enhanced fatty acid oxidation), while driving tumor-associated macrophages (TAMs) to highly express PD-1, forming a unique immunosuppressive microenvironment. However, due to limitations of preclinical models, confounding factors in clinical data, and the singularity of traditional obesity definition indicators (such as BMI), elucidating the mechanisms of the "obesity paradox" and its clinical translation faces many challenges. Therefore, this review combs the dual effects of obesity in tumor immunotherapy, focuses on elucidating its remodeling mechanisms of the TME metabolic-immune regulatory network, explores multidimensional assessment strategies beyond BMI and the application prospects of better preclinical models, aiming to provide new ideas for precision immunotherapy in obese cancer patients.
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