Recent advancements of neoadjuvant strategies in locally advanced rectal cancer

The field of neoadjuvant therapy for locally advanced rectal cancer (LARC) has undergone profound changes, shifting from a primary focus on local control to a comprehensive strategy emphasizing long-term oncological outcomes and patient-centered care. While traditional neoadjuvant chemoradiotherapy (nCRT) followed by total mesorectal excision remains a cornerstone, its limitations in preventing distant recurrence and improving overall survival are increasingly recognized. Total neoadjuvant therapy (TNT), delivering systemic chemotherapy before or after nCRT, has thus emerged as a new paradigm. It aims to address micrometastatic disease more effectively, thereby enhancing pathological complete response rates and creating unprecedented opportunities for organ preservation. A landmark advancement is the efficacy of immune checkpoint inhibitors in mismatch repair-deficient LARC, achieving clinical complete responses that can obviate the need for surgery. However, overcoming resistance in mismatch repair-proficient tumors constitutes a major therapeutic hurdle. As organ preservation strategies like "watch-and-wait" gain traction, the imperative for accurate response assessment using tools such as circulating tumor DNA and multi-omics profiling has intensified. This narrative review synthesizes recent progress, critically examining the optimization of TNT, the integration of immunotherapy, the evolution of organ preservation, predictive biomarkers, and the changing role of surgery, with the goal of guiding contemporary management and future research.