The Evolving Landscape of Immunotherapy in Locally Advanced Rectal Cancer Patients

Simple Summary At the last 2022 annual ASCO meeting, impressive results of anti-PD1 activity in clinical stage 2 and 3 microsatellite instable rectal cancer patients have been published. Moreover, a growing number of studies assessed the synergism between neoadjuvant (chemo)radiotherapy and immunotherapy in microsatellite stable localized rectal cancer patients. Major findings of immunotherapy activity and efficacy in localized rectal cancer, according to microsatellite status, are discussed in this commentary. Standard treatments of localized rectal cancer are surgery or the multimodal approach with neoadjuvant treatments (chemo-radiotherapy, short-course radiotherapy, induction, or consolidation chemotherapy) followed by surgery. In metastatic colorectal cancer (mCRC), immune checkpoint inhibitors (ICIs) are now the first choice in patients with a deficient mismatch repair system/microsatellite instability (dMMR/MSI-H) and are being explored in combination with chemotherapy to rewire the immune system against malignant cells in subjects with proficient mismatch repair system/microsatellite low (pMMR/MSI-L) cancers, with promising signals of efficacy. Recently, some efforts have been made to translate ICIs in earlier stages of CRC, including localized rectal cancer, with breakthrough efficacy and an organ preservation rate of mono-immunotherapy in dMMR/MSI-H patients and promising anti-tumor activity of immunotherapy plus neoadjuvant (chemo)radiotherapy in pMMR/MSI-L subjects. Here, we present the rationale, results, and limitations of the most remarkable trials assessing ICIs in dMMR/MSI-H and pMMR/MSI-L localized rectal cancer patients, at the same time highlighting the most promising research perspectives that have followed these studies.