The Role of the Obesity Paradox in Cancer Progression and Immunotherapy

Dear Colleagues,

Obesity is unmistakably associated with an increased risk of certain cancers. Chronic systemic inflammation is a major carcinogenic mechanism that connects obesity and cancer, with many inflammatory factors being released from expanded adipose tissue. However, at certain stages of cancer treatment, a protective association between overweight and class 1 obesity (30.0–34.9 kg/m²) has been reported. The "obesity paradox" describes how certain cancer patients outperform individuals with a stable normal weight or patients with severe obesity, but this finding does not apply to all cancers or all patients. This disparity may be due to several confounding factors, such as the use of BMI (a poor measure of visceral obesity), the additional nutrient and energy reserve available in excess adipose tissue (which may improve how patients cope during cancer treatment) or adipocyte absorption and the metabolism of chemotherapy drugs (which reduces the overall toxicity of cancer treatments). Unintentional loss of muscle and/or adipose tissue, on the other hand, is associated with increased treatment toxicities and mortality in sarcopenia and cachexia. While obesity is linked to an increased risk of developing cancer, it is unclear how obesity affects health outcomes once a patient is diagnosed.

Immunotherapies that target immune checkpoint pathways, such as programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1), have revolutionized cancer treatment. Obesity has been linked to a number of cancers, including esophageal, colorectal, melanoma and kidney cancers, for which anti-PD-1 and anti-PD-L1 therapies have been approved. However, there is a gap in understanding as to why mild obesity can be protective in certain cancer types during specific stages of cancer treatment whereas severe obesity does not provide the same benefit in terms of health outcomes in certain cancers. As a result, there is an urgent need to elucidate the molecular mechanisms by which obesity affects anti-tumor immunity and the efficacy of immune checkpoint inhibitors, which will aid in the development of new strategies that may improve prognosis for cancer patients and increase our understanding of the obesity paradox.

Dr. Abhishek Tyagi
Guest Editor

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• obesity paradox
• tumor immunology
• tumor metastasis
• immunotherapy