Modified Short-Course Radiotherapy Combined With Immunochemotherapy and Targeted Therapy as First-Line Treatment for MSS Metastatic Colorectal Cancer

Inclusion criteria

• 1. Voluntarily participate in this study and provide written informed consent. Good compliance and ability to comply with follow-up procedures.

• Age ≥ 18 years. 3. Primary tumor located in the colon or rectum. 4. Histologically confirmed adenocarcinoma; pMMR by immunohistochemistry or MSS by genetic testing.

• Metastatic disease confirmed by contrast-enhanced or non-contrast CT or contrast-enhanced MRI within 3 weeks before enrollment; at least one measurable lesion in the liver and/or lung, or peritoneal cavity (RECIST 1.1); metastatic lesions assessed as initially unresectable by multidisciplinary discussion.

• ECOG performance status 0-1. 7. Life expectancy ≥ 3 months. 8. Adequate organ and bone marrow function:
• Hemoglobin ≥ 6.0 mmol/L,
• Absolute neutrophil count ≥ 1.5 ×10⁹/L,
• Platelet count ≥ 100 ×10⁹/L;
• Renal function: serum creatinine ≤ 1.5 × ULN and creatinine clearance ≥ 30 mL/min;
• Hepatic function: serum bilirubin ≤ 2 × ULN, serum transaminases ≤ 5 × ULN. 9. No contraindications to surgery.

Exclusion criteria

• 1. Prior treatment with PD-1, PD-L1, or other immune checkpoint inhibitors. 2. Prior receipt of any anti-tumor therapy for colorectal cancer, including radiotherapy, chemotherapy, or tumor resection surgery.

• Microsatellite instability-high (MSI-H) or DNA mismatch repair deficiency (dMMR).

• Presence of brain metastases. 5. Participation in another clinical trial of anti-tumor agents within 4 weeks prior to enrollment.

• History of hypersensitivity to monoclonal antibodies, any component of tislelizumab, capecitabine, oxaliplatin, or bevacizumab.

• Receipt of local treatments including transarterial chemoembolization, microwave ablation, radiofrequency ablation, SBRT, or metastasectomy for liver or lung metastases within 4 weeks prior to enrollment.

• Confirmed immunodeficiency disease or active autoimmune disease, including but not limited to systemic lupus erythematosus, inflammatory bowel disease, myasthenia gravis, autoimmune hepatitis, rheumatoid arthritis, multiple sclerosis, glomerulonephritis, vasculitis; use of other immunosuppressive agents or systemic corticosteroids for immunosuppressive purposes within 4 weeks prior to enrollment.

• Known human immunodeficiency virus (HIV) infection; clinically significant liver disease including viral hepatitis [active HBV infection (HBV DNA ≥ 2000 IU/mL or 10⁴ copies/mL), hepatitis C (positive anti-HCV antibody with HCV RNA above the lower limit of detection)].

• Uncontrolled hypertension, or inadequate blood pressure control despite treatment with ≥ 3 antihypertensive agents.

• Disease with severe bleeding risk such as gastrointestinal bleeding, bleeding diathesis, or thrombotic disease requiring long-term oral anticoagulants or antiplatelet agents.

• Uncontrolled cardiac symptoms or diseases including but not limited to:
• NYHA class ≥ II heart failure;
• unstable angina;
• myocardial infarction within 1 year;
• clinically significant supraventricular or ventricular arrhythmias that are uncontrolled or poorly controlled despite intervention.

• Severe infection (CTCAE grade > 2) within 4 weeks prior to the first study drug administration, such as severe pneumonia, bacteremia, or infectious complications requiring hospitalization; active pulmonary inflammation on baseline chest imaging; signs or symptoms of infection or requirement for oral or intravenous antibiotics within 14 days before the first study drug administration (excluding prophylactic antibiotics); active tuberculosis confirmed by history or CT, history of active tuberculosis within 1 year prior to enrollment, or history of active tuberculosis more than 1 year prior without standard treatment.

• Diagnosis of another malignancy within 5 years prior to the first study drug administration, except malignancies with low risk of metastasis or death (5-year survival > 90%), such as adequately treated basal cell carcinoma or squamous cell carcinoma of the skin, or carcinoma in situ of the cervix.

• Pregnant or lactating female. 16. Other vulnerable populations, including patients with psychiatric disorders, cognitive impairment, or critical illness.

• Any other condition judged by the investigator that may lead to premature study discontinuation, such as other serious diseases (including psychiatric disorders) requiring concurrent treatment, alcoholism, drug abuse, family or social factors that may affect subject safety or compliance.