The study compares the efficacy and safety of regorafenib alone or in combination with hypofractionated radiotherapy and low-dose radiotherapy (LDRT) plus toripalimab in patients with microsatellite stable metastatic colorectal cancer (MSS mCRC). Patients are randomly assigned (1:1) into the control arm and the experimental arm. Control arm: a total of 54 patients will receive regorafenib monotherapy. Experimental arm: a total of 54 patients will first receive 1 cycle of regorafenib and toripalimab followed by hypofractionated/low-dose radiotherapy. Regorafenib and toripalimab will be continued after the completion of radiotherapy. The survival benefits, response rates, and adverse effects will be analyzed.

Control arm: regorafenib 120 mg orally once daily on days 1-21 of each 28 days cycle.

Experimental arm: regorafenib is administered 80 mg once daily on days 1-21 of each 28 days cycle with intravenous toripalimab 240 mg every 3 weeks. Radiotherapy regimes include hypofractionated radiotherapy (5 fractions of 4-12Gy) and low-dose radiotherapy (5 fractions of 0.5-2Gy).

Inclusion Criteria:

1. Age ≥18 years old
2. An Eastern Cooperative Oncology Group (ECOG) performance status ≤1
3. Life expectancy of at least 3 months
4. Histopathological confirmed MSS/pMMR adenocarcinoma of the colon or rectum
5. At least one evaluable metastatic lesion for radiotherapy according to RECIST 1.1
6. Progressed on or after the standard first-and second-line therapies or stopped standard therapy because of unacceptable toxic effects
7. Previous radiotherapy completed at least 4 weeks before randomization
8. Adequate bone-marrow, hepatic, and renal function: neutrophils ≥ 1.5 × 10^9/L, Hb ≥ 90 g/L, PLT ≥ 100 × 10^9/L, ALT/ AST≤2.5 ULN, Cr≤1 ULN
9. Sign the informed consent and have good compliance

Exclusion Criteria:

1. History of previous treatment with regorafenib and ICIs such as anti-PD-1 or anti-PD-L1 mAbs
2. Current severe cardiovascular diseases such as unstable angina, congestive heart failure, or serious cardiac arrhythmia requiring medication
3. Acute cardiac infarction or cerebral ischemic stroke occurred within 6 months before recruitment
4. Active autoimmune diseases and immunodeficiencies, known history of organ transplantation, or systematic use of immunosuppressive agents
5. Active Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection: HBsAg positive or HBV DNA positive, anti-HCV antibody testing positive and confirmatory HCV RNA positive
6. Positive human immunodeficiency virus (HIV) infection, active syphilis infection, or active pulmonary tuberculosis infection
7. Severe infections requiring systemic antibiotics, antifungal or antiviral therapy
8. Uncontrollable pleural effusion, pericardial effusion, or ascites
9. Other malignancies within 5 years before recruitment, except for non-melanoma skin cancer, superficial bladder cancer, cervical carcinoma in situ, or breast cancer in situ that had been effectively treated.
10. Known history of severe neurological or mental illness such as schizophrenia, dementia, or epilepsy
11. Known history of allergy to any component involved in this study.
12. Pregnancy or breast-feeding women