Advancing the Science of Weight Loss and Cancer Risk: A Framework for Future Investigation

Background: Obesity is a leading modifiable risk factor for cancer, and metabolic and bariatric surgery consistently reduce cancer incidence among individuals with severe obesity. However, the mechanisms underlying this protection remain poorly characterized, limiting the development of targeted cancer prevention strategies.Objectives: To identify critical knowledge gaps in understanding how weight loss reduces cancer risk and to propose a framework for coordinated investigation across the research spectrum.Methods: We reviewed current evidence on metabolic surgery and cancer outcomes, evaluated existing data resources, and assessed methodological and infrastructure limitations constraining progress in this field.Results: Key gaps include an incomplete understanding of whether cancer protection derives from weight loss per se or surgery-specific metabolic changes; limited ability to compare surgical and pharmacologic weight loss approaches; absence of standardized outcome definitions across studies; and insufficient infrastructure for data sharing and integration. The emergence of highly effective GLP-1 receptor agonists creates unprecedented opportunities for mechanistic comparison but introduces new uncertainties regarding long-term cancer effects.Conclusions: Progress requires coordinated investment across basic science, clinical trials, electronic health record-based research, and epidemiologic studies. Priorities include developing interoperable data standards, supporting privacy-preserving data sharing methods, expanding access to multiomics tissue repositories, and building collaborative networks capable of adequately powdered cancer outcomes research.