• Age ≥ 18 years, any gender.

• Patients with metastatic colorectal adenocarcinoma confirmed by pathological histology or cytology.

• Expected survival time ≥ 12 weeks.

• ECOG score of 0-2.

• Previously treated for metastatic colorectal cancer with fluoropyrimidine (allowing intravenous and/or oral fluoropyrimidine formulations, excluding DPD enzyme inhibitors), irinotecan, and oxaliplatin chemotherapy, which failed (treatment failure defined as intolerable adverse reactions, disease progression during treatment, or disease progression within 6 months after completing adjuvant chemotherapy); regardless of prior use of targeted drugs such as cetuximab or bevacizumab.

• Patients must have an interval of at least 2 weeks since the last chemotherapy (at least 1 week for oral chemotherapy drugs) or more than 4 weeks since the end of radiotherapy, with the study's observable lesions located outside the radiotherapy target area.

• According to RECIST 1.1 criteria, at least one measurable tumor lesion with a maximum diameter ≥ 1 cm as determined by spiral CT scan.

• Laboratory test results within 1 week before enrollment must meet the following criteria:

∙ Hemoglobin ≥ 90 g/L; Platelets (PLT) ≥ 75 × 10\^9/L;

‣ White blood cells (WBC) ≥ 3.0 × 10\^9/L; Neutrophils (ANC) ≥ 1.5 × 10\^9/L;

‣ Serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN);

‣ Total bilirubin (TBI) ≤ 1.5 × ULN; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN (≤ 5 × ULN if there is liver metastasis).

• No prior use of raltitrexed or S-1 (or DPD enzyme inhibitors) in the treatment of colorectal cancer.

⁃ Signed informed consent.