This phase II clinical trial evaluates the efficacy and safety of three neoadjuvant regimens in patients with locally advanced microsatellite instability-high/mismatch repair-deficient (MSI-H/dMMR) colorectal cancer (CRC): 1) Regimen A: Dual immune checkpoint blockade with nivolumab plus ipilimumab. 2) Regimen B: Nivolumab plus radiotherapy. 3) Regimen C: Nivolumab monotherapy. The primary objectives are to determine whether: 1) Dual immune checkpoint blockade (Regimen A) is superior to nivolumab monotherapy (Regimen C); and 2) Immunotherapy plus radiotherapy (Regimen B) is superior to nivolumab monotherapy (Regimen C). Methods: Participants will be randomized in a 1:1:1 ratio to one of the three arms. For patients with resectable tumors, surgical resection will be performed. In patients with low rectal cancer and poor prospects for sphincter preservation, a watch-and-wait (WW) strategy is an option if a clinical complete response (CR) is achieved following neoadjuvant therapy.

Inclusion Criteria:

1. Histopathologically confirmed primary colorectal adenocarcinoma.
2. Radiographic assessment showed a stage II-III based on AJCC Stage 8th ed.
3. At least 18 years old.
4. MSI-H or dMMR.
5. The Eastern Cooperative Oncology Group performance status (ECOG PS) score is 0 or 1.
6. Physical state or organ function can tolerate the planned treatment of the study protocol.
7. Agreed to sign written informed consent before recruitment.

Exclusion Criteria:

1. Previously received any antitumor therapy for the disease under study, including surgery, radiotherapy, chemotherapy, targeted therapy, immunotherapy, etc.
2. Pregnancy or breastfeeding women.
3. History of other malignancies within 5 years.
4. Serious medical illness, such as severe mental disorders, cardiac disease, uncontrolled infection, etc.
5. Immunodeficiency disease or long-term using of immunosuppressive agents.
6. Allergic to any component of the therapy.
7. Any other condition or disease that is not suitable to take the therapy included in the protocol.
8. Concurrent participation in another clinical study, unless participating in an observational (non-interventional) clinical study or in the survival follow-up phase of an interventional study.
9. Received any investigational drug or device treatment within 4 weeks prior to initial administration of the investigational drug.