Obesity Paradox in Cancer: A Complex Interplay Between Risk and Therapeutic Outcomes

Obesity is a recognized risk factor for cancer development and progression. Paradoxically, growing clinical evidence across several cancer types indicates that elevated body mass index (BMI) or specific body composition characteristics-such as increased visceral fat or preserved skeletal muscle-may be associated with moderately improved overall survival in patients undergoing immune checkpoint inhibitor (ICI) therapy. This seemingly contradictory phenomenon is often described as the "obesity paradox." In this review, we delineate the etiological versus therapeutic implications of obesity, synthesizing data from non-small cell lung cancer, renal cell carcinoma, melanoma, and hepatocellular carcinoma. Proposed explanations include low-grade inflammation with signal transducer and activator of transcription 3-mediated programmed death-1 upregulation, insulin/insulin-like growth factor-1 signaling, adipokine imbalance, stromal fibrosis and hypoxia, and metabolic reprogramming that may alter T-cell function and tumor immunogenicity. Nonbiological factors-including dosing strategies, sarcopenia, and sex-specific differences-are also examined. We advocate for future research employing comprehensive body composition assessments, standardized pharmacokinetic/pharmacodynamic analyses, and consideration of sex and metabolic health. Clarifying the temporal and mechanistic basis of the obesity-ICI benefit relationship will inform the optimization of cancer immunotherapy.