Total neoadjuvant therapy (TNT) significantly improves response and survival in high-risk rectal cancer patients.

• Clinical complete response rate with TNT was 25.8%, compared to 4.0% with conventional chemoradiotherapy (p < 0.001).
• TNT showed superior overall survival (hazard ratio 0.48) and disease-free survival (hazard ratio 0.62) versus chemoradiotherapy.

Adopting TNT can facilitate organ preservation strategies while maintaining or improving surgical outcomes.

• Key risk factors influencing survival included MRI-defined T4 stage and extramural venous invasion.