Implications of Rectal Cancer Radiotherapy on the Immune Microenvironment: Allies and Foes to Therapy Resistance and Patients' Outcome

Simple Summary The efficiency of (chemo-)radiotherapy for rectal cancer is not only determined by the impact on the tumor cells themselves but also by the highly individual surrounding tumor microenvironment, including immune cells. However, many aspects of the radiation-induced immune response remain to be fully understood. This review summarizes existing literature about the effects of (chemo-)radiotherapy on the rectal cancer immune microenvironment, which can be both tumor-suppressive or pro-tumorigenic, by either promoting an effective anti-tumor immune response or mediating resistance. We further aim to highlight potential immune-modulating combination therapies, such as immune checkpoint inhibitors, that offer individualized approaches to target the heterogeneous tumor immune microenvironment.Abstract Aside from surgical resection, locally advanced rectal cancer is regularly treated with neoadjuvant chemoradiotherapy. Since the concept of cancer treatment has shifted from only focusing on tumor cells as drivers of disease progression towards a broader understanding including the dynamic tumor microenvironment (TME), the impact of radiotherapy on the TME and specifically the tumor immune microenvironment (TIME) is increasingly recognized. Both promoting as well as suppressing effects on anti-tumor immunity have been reported in response to rectal cancer (chemo-)radiotherapy and various targets for combination therapies are under investigation. A literature review was conducted searching the PubMed database for evidence regarding the pleiotropic effects of (chemo-)radiotherapy on the rectal cancer TIME, including alterations in cytokine levels, immune cell populations and activity as well as changes in immune checkpoint proteins. Radiotherapy can induce immune-stimulating and -suppressive alterations, potentially mediating radioresistance. The response is influenced by treatment modalities, including the dosage administered and the highly individual intrinsic pre-treatment immune status. Directly addressing the main immune cells of the TME, this review aims to highlight therapeutical implications since efficient rectal cancer treatment relies on personalized strategies combining conventional therapies with immune-modulating approaches, such as immune checkpoint inhibitors.