Combination of High and Low-Dose Radiotherapy With Immune Therapy and TKI in Advanced Colorectal Cancer: A Phase II Study

Inclusion Criteria: 1. Ability to understand and willingness to sign a written informed consent form. 2. Age 18-80 years, male or female. 3. Histologically confirmed microsatellite stable (MSS) / proficient mismatch repair (pMMR) colorectal adenocarcinoma. 4. Clinical stage IV disease confirmed by systemic imaging. At least two measurable metastatic lesions per RECIST 1.1, including: At least one lesion ≥2 cm in diameter and at least one lesion \<2 cm in diameter; For lesions within the same organ, at least one lesion ≥2 cm and one lesion \<2 cm must be located within independent, non-overlapping radiation fields; For lesions in different organs, high-dose and low-dose radiotherapy should preferably be delivered to lesions in different organs. Second-line or later treatment setting, defined as disease progression after prior platinum- and irinotecan-based chemotherapy, including: 5. Failure after first-line triplet chemotherapy containing platinum and irinotecan; Or failure after first-line platinum-based chemotherapy followed by second-line irinotecan-based chemotherapy. 6. Ability to swallow oral medication. 7. ECOG performance status 0-1. 8. Adequate organ function as defined by laboratory criteria. Exclusion Criteria: Diffuse miliary liver or lung metastases, or bulky metastatic lesions ≥10 cm in diameter. Presence of brain metastases. 1. History of severe hypersensitivity to monoclonal antibodies or anti-angiogenic agents. 2. Prior exposure to immune checkpoint inhibitors (including anti-PD-1, anti-PD-L1, anti-CTLA-4 antibodies), immune checkpoint agonists (e.g., targeting ICOS, CD40, CD137, GITR, OX40), or any prior cancer immunotherapy. 3. Active autoimmune disease or history of autoimmune disease, including but not limited to interstitial pneumonitis, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, or hypothyroidism (patients on stable hormone replacement therapy may be eligible). Patients with psoriasis or childhood asthma/allergy that has completely resolved and requires no adult intervention may be eligible; patients requiring bronchodilator therapy are excluded. 4. History of immunodeficiency, including positive HIV test, congenital or acquired immunodeficiency, prior organ transplantation, or allogeneic bone marrow transplantation. 5. Uncontrolled cardiovascular disease, including: NYHA class II or higher heart failure; 6. Unstable angina; 7. Myocardial infarction within 1 year; 8. Clinically significant uncontrolled supraventricular or ventricular arrhythmias. 9. Severe infection (CTCAE grade \>2) within 4 weeks prior to first study treatment, including severe pneumonia, bacteremia, or infection requiring hospitalization. Active pulmonary inflammation on baseline imaging, signs or symptoms of infection within 14 days before treatment requiring systemic antibiotics (except prophylactic antibiotics), or active tuberculosis (current or within 1 year without adequate treatment). 10. Active hepatitis B (HBV DNA ≥2000 IU/mL) or active hepatitis C (positive HCV antibody with detectable HCV RNA above the lower limit of detection). 11. Diagnosis of another malignancy within 5 years prior to first study treatment, except for malignancies with low risk of metastasis or death (5-year survival rate \>90%), such as adequately treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ of the cervix. 12. Pregnant or breastfeeding women.