Inclusion Criteria:
1. Have a full understanding of this study and voluntarily sign the informed consent form;
2. Aged 18 - 75 years;
3. Patients must be pathologically confirmed as advanced, metastatic or recurrent microsatellite stable (MSS) colorectal cancer (detected by immunohistochemistry, PCR or NGS according to the detection standards of each institutional testing center);
4. The results of patients' genetic testing show no POLD1/POLE mutations;
5. At least one immune marker is positive:
* PD-L1 CPS score ≥ 10 points, and positive for tumor-infiltrating CD8+ T cells;
* TMB ≥ 10 Muts/mb, and positive for tumor-infiltrating CD8+ T cells; ③ Functional mutations in epigenetic genes such as ARID1A, KMT2A/B/C/D, TET1/2/3, etc., and positive for tumor-infiltrating CD8+ T cells; ④ Presence of positive tertiary lymphoid structures (TLS) in the tumor microenvironment;
6. Patients have previously received two or more treatment regimens for advanced or metastatic colorectal cancer, at least one of which includes fluorouracil; or patients have previously received one treatment regimen for advanced or metastatic colorectal cancer and cannot tolerate the second-line standard chemotherapy regimen;
7. ECOG performance status of 0 - 1, with no deterioration within 7 days;
8. Expected survival ≥ 3 months;
9. Organ function levels must meet the following requirements:
* Sufficient bone marrow reserve: absolute neutrophil count ≥ 1.5×10⁹/L, platelet count ≥ 90×10⁹/L, hemoglobin ≥ 9 g/dL; no blood transfusion or use of blood products within 14 days;
* Liver: plasma albumin ≥ 2.8 g/dL; bilirubin ≤ 1.5 times the upper limit of normal (ULN); ALT and AST ≤ 2.5×ULN, and if there is liver metastasis, ALT and AST ≤ 5×ULN; ③ Kidney: serum creatinine ≤ 1.5×ULN;
* Heart: left ventricular ejection fraction (LVEF) ≥ 50%; ⑤ Coagulation: prothrombin time (PT) ≤ 1.5×ULN, international normalized ratio (INR) ≤ 1.5×ULN, activated partial thromboplastin time (APTT) ≤ 1.5×ULN; ⑥ Thyroid-stimulating hormone (TSH) ≤ ULN (if abnormal, FT3 and FT4 levels should be examined simultaneously; if FT3 and FT4 levels are normal, patients can be enrolled);
10. Women of childbearing age need to take effective contraceptive measures;
11. Have good compliance and be cooperative with follow-up;
12. Agree to provide sufficient previously stored tumor tissue samples for testing.
Exclusion Criteria:
1. Unable to comply with the study protocol or research procedures;
2. Pregnant or lactating women;
3. Any factors affecting oral administration;
4. Patients who have previously received immunotherapy and fruquintinib;
5. Complicated with any of the following conditions: uncontrolled hypertension, coronary artery disease, arrhythmia, and heart failure;
6. Patients who participated in clinical studies of other drugs within 4 weeks before enrollment;
7. Alcohol or drug abuse within 4 weeks after the last clinical trial;
8. Anti-infective treatment did not stop 14 days before the start of the study;
9. Severe uncontrolled systemic diseases, such as severe active infections;
10. Urinalysis shows urine protein \> ++, and it is confirmed that 24-hour urine protein \> 1.0 g;
11. Active bleeding within 3 months; severe arterial/venous thrombotic events within 6 months; hereditary or acquired bleeding (e.g., coagulation dysfunction); major surgery (except biopsy and electroresection of polyps) within 4 weeks before the study, incompletely healed surgical incisions, or major trauma; use of aspirin (\> 325 mg/day) or current or recent use of dipyridamole, clopidogrel, and cilostazol (10 days before the study);
12. Acute myocardial infarction, acute coronary syndrome, or coronary artery bypass grafting within 6 months before the first treatment;
13. Use of systemic glucocorticoids or other systemic immunosuppressive drugs within 2 weeks before treatment. Immunosuppressive drugs have been started or are expected to be used during the trial. Physiological replacement doses are allowed for inhaled glucocorticoids;
14. Fractures or long-term unhealed wounds;
15. Inactivated vaccines 接种 within 4 weeks before enrollment;
16. Having other malignant tumors within 5 years before enrollment, except for basal cell carcinoma or squamous cell carcinoma of the skin after radical resection, or carcinoma in situ of the cervix;
17. Known to be infected with human immunodeficiency virus (HIV), or positive for syphilis test, or known to be HIV-positive patients;
18. Previously received allogeneic bone marrow transplantation or organ transplantation;
19. Subjects allergic to the study drug or any of its auxiliary preparations;
20. Electrolyte abnormalities judged by the researcher to be clinically significant;
21. Detectable untreated chronic hepatitis B, chronic hepatitis B virus (HBV) carriers (HBV DNA \> 2000 IU/mL), or HCV carriers with detectable HCV RNA. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, treated and stable hepatitis B patients (HBV DNA \< 2000 IU/mL) can be included in the study;
22. Previous radiation pneumonitis or chest CT scan showing active pneumonia within 4 weeks before the study;
23. The patient has an autoimmune disease requiring intervention;
24. Accompanied by brain metastasis, or severe malignant pleural or peritoneal effusion;
25. Any other diseases, clinically significant metabolic abnormalities, abnormal physical examination or laboratory test results, which, in the researcher's judgment, reasonably suggest that the patient has a disease or condition unsuitable for the use of the study drug (such as having epileptic seizures requiring treatment), or will affect the interpretation of study results, or put the patient at high risk;
26. Patients deemed inappropriate for inclusion in this study by the researcher.
