Neoadjuvant chemoradiotherapy (nCRT) and interval total mesorectal excision (TME) is the standard of care for patients with bulky cT3/4 tumors or predicted node-positive disease in most countries. Total neoadjuvant therapy (TNT) has emerged as an attractive alternative strategy—systemic chemotherapy given before nCRT or after it in the preoperative setting. Neoadjuvant therapy has the potential to eradicate tumors entirely. A pathological complete response (pCR) represents an important predictor of favorable oncological outcome. Long-term survival data following TNT are lacking and predominantly limited to small case series. A systematic review of oncological outcomes following TNT, including several prospective studies reporting five-year survival data, found similar long-term survival outcomes when compared with standard nCR. The past few decades have witnessed unprecedented advances in the field of cancer immunology. Immunotherapy with checkpoint blockade has had limited efficacy in the vast majority of patients with metastatic colorectal cancer. The incidence of locally recurrent rectal cancer remains approximately 5%.