The standard treatment for patients with rectal cancer ≥cT3N0 typically is based on neoadjuvant chemoradiotherapy, total mesorectal excision, and adjuvant chemotherapy. The most appropriate strategy is determined through a multidisciplinary discussion that takes into consideration patient comorbidities and tumor characteristics. It also involves the knowledge of the molecular mechanisms and role of the tumor microenvironment, which are crucial for the effective management of rectal cancer and other tumor types. This chapter focuses on a relatively new approach known as total neoadjuvant therapy and its implications for rectal cancer surgery. The goal of this approach is to administer systemic chemotherapy and neoadjuvant radiotherapy before surgery, utilizing different protocols to enhance patient compliance, improve rectal surgery outcomes, decrease recurrence rates, and ultimately increase overall survival.