Evaluating the impact of GLP-1 receptor agonists in combination with total neoadjuvant therapy for locally advanced...

Total neoadjuvant therapy (TNT) has become a standard treatment approach for rectal cancer, providing higher rates of pathological complete response and improved long-term survival. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have shown significant advantages in weight loss, systemic metabolic regulation, and anti-inflammatory effects. Emerging evidence also points to possible anticancer properties, with observational data suggesting a lower incidence of obesity-related cancers, including colorectal cancer. This narrative review aims to examine the biological basis and potential therapeutic benefits of combining GLP-1 RAs with TNT for the management of locally advanced rectal cancer. We explore how GLP-1 RAs may affect tumour biology and treatment tolerance, including their impact on visceral fat, insulin resistance, and systemic inflammation. Preclinical and clinical data are reviewed to determine whether GLP-1-induced metabolic changes can improve the effectiveness of chemotherapy and enhance surgical and oncological results. Although evidence is evolving, the integration of GLP-1 receptor agonists into rectal cancer treatment pathways represents a promising area for further investigation, particularly in metabolically vulnerable populations.