GLP-1 Agonists with TNT in Rectal Cancer: Metabolic Optimization Meets Oncology: British Journal of Surgery | June 2026

• This review explores a novel concept: whether GLP-1 receptor agonists can improve outcomes when combined with total neoadjuvant therapy in locally advanced rectal cancer.

• Total neoadjuvant therapy is now a standard approach for locally advanced rectal cancer because it improves treatment completion, pathological complete response, disease control, and sphincter preservation.

• Obesity is an important negative prognostic factor in colorectal cancer, associated with higher perioperative morbidity, recurrence risk, technical surgical difficulty, and worse long-term outcomes.

• GLP-1 receptor agonists, such as semaglutide, produce substantial weight loss and improve insulin resistance, systemic inflammation, and metabolic dysfunction.

• The biological rationale is strong: reducing visceral adiposity, hyperinsulinaemia, and chronic inflammation may improve tumour biology and treatment tolerance.

• GLP-1 RAs may also help patients tolerate neoadjuvant chemotherapy and radiotherapy better by improving metabolic reserve and reducing obesity-related treatment complications.

• Emerging observational data suggest GLP-1 RA use may be associated with lower incidence of obesity-related cancers, including colorectal cancer, although causality remains unproven.

• Potential anticancer mechanisms include improved insulin signaling, reduced inflammatory cytokines, altered tumour metabolism, and modulation of the tumour microenvironment.

• The most clinically relevant population may be metabolically vulnerable patients with rectal cancer, especially those with obesity, type 2 diabetes, insulin resistance, or sarcopenic obesity.

• GLP-1 RAs may complement prehabilitation, particularly because intensive lifestyle-based weight-loss programs are difficult to complete during neoadjuvant cancer treatment.

• Important safety questions remain, including nutritional adequacy during chemotherapy, preservation of muscle mass, gastrointestinal side effects, and timing around surgery.

• Current evidence is mainly biological, preclinical, and observational. There is no definitive clinical trial evidence yet showing that GLP-1 RAs improve pathological complete response, survival, or surgical outcomes in rectal cancer.

• Future trials should evaluate whether GLP-1 RAs can improve treatment completion, reduce complications, enhance tumour regression, and improve long-term oncological outcomes.

Bottom line: GLP-1 receptor agonists represent a promising metabolic adjunct to total neoadjuvant therapy in locally advanced rectal cancer, especially in obese or insulin-resistant patients, but this strategy remains investigational and requires prospective clinical validation.