Body Mass Index Effects on Immune Checkpoint Inhibition Outcomes

Body mass index (BMI) has emerged as a paradoxical modifier of response to immune checkpoint inhibitors (ICIs) across multiple malignancies. While obesity is a recognised risk factor for cancer onset and progression, clinical observations suggest that overweight and mildly obese patients often experience enhanced efficacy of anti-PD-1/PD-L1 and anti-CTLA-4 therapies. Mechanistic studies reveal that excess adiposity alters the tumour microenvironment through dysregulated cytokine secretion, impaired CD8+ T cell metabolism and chemokine gradients, as well as shifts in adipose-derived inflammatory mediators. These changes can both hinder immune surveillance and, under ICI treatment, unmask tumour immunogenicity, leading to improved clinical outcomes—a phenomenon referred to as the “obesity paradox.” Importantly, body composition nuances such as visceral versus subcutaneous fat depots, sarcopenia and weight change interventions further refine predictive value. Higher BMI also correlates with a greater incidence of immune-related adverse events, underscoring the need to balance therapeutic benefits against toxicity risks. Understanding the interplay between adiposity, immune regulation and checkpoint blockade has profound implications for patient stratification, supportive interventions like dietary or pharmacological weight modulation, and optimisation of immunotherapy protocols globally.

Research from Nature Portfolio

Recent studies using diet-induced obesity mouse models have dissected the impact of excess weight on CD8+ T cell function within tumours. Obesity drives T cell exhaustion and blunts chemokine-mediated recruitment, leading to increased sarcoma incidence in preclinical carcinogenesis models. Notably, dietary weight loss—but not semaglutide-induced weight loss—restores CD8+ T cell effector function and augments response rates to anti-PD-1 therapy. Paradoxically, tumours developing in obese hosts display heightened immunogenicity that renders them more susceptible to checkpoint inhibition, offering a mechanistic basis for improved clinical outcomes observed in overweight patients. These findings highlight the complex bidirectional effects of adiposity on antitumour immunity and reinforce the therapeutic value of tailored nutritional interventions alongside ICIs.

Body Mass Index Effects on Immune Checkpoint Inhibition Outcomes publication trend

The graph below shows the total number of articles in body mass index effects on immune checkpoint inhibition outcomes across all publications each year (not limited to Nature Index journals).

Technical terms

Body Mass Index (BMI): A weight-to-height ratio (kg/m2) used to classify underweight, normal weight, overweight and obese individuals.

Immune Checkpoint Inhibition: Therapeutic blockade of regulatory pathways (e.g., PD-1/PD-L1, CTLA-4) to enhance T cell-mediated antitumour immunity.

CD8+ T Cell Exhaustion: A dysfunctional state of cytotoxic T lymphocytes marked by loss of proliferative capacity and cytokine production.

Visceral Adipose Tissue (VAT): Fat stored within the abdominal cavity, surrounding internal organs, and linked to metabolic and immune alterations.

Immune-Related Adverse Event (irAE): Toxicities arising from nonspecific immune activation during checkpoint blockade, affecting various organ systems.

References

1. Obesity-related T cell dysfunction impairs immunosurveillance and increases cancer risk. Nature Communications (2024).
2. Body mass index and adiposity influence responses to immune checkpoint inhibition in endometrial cancer. Journal of Clinical Investigation (2024).
3. Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function. Journal of Experimental Medicine (2022).
4. Predictive biomarkers for immune-related adverse events in cancer patients treated with immune-checkpoint inhibitors. BMC Immunology (2024).