A Multicenter, Phase Ib/II Clinical Trial to Evaluate the Efficacy and Safety of Concurrent Combination Therapy of S-531011 Plus Fruquintinib or S-531011 Plus Fruquintinib Plus Pembrolizumab in Patients With MSS/pMMR Colorectal Cancer

Inclusion Criteria: 1. Patients with histologically confirmed unresectable adenocarcinoma of the colon or rectum. 2. Confirmed microsatellite stable (MSS) or proficient mismatch repair (pMMR) status. 3. Prior treatment with standard systemic chemotherapy and refractory or intolerant\* to such therapies. Standard chemotherapy must include all of the following: \- Fluoropyrimidine, irinotecan, and oxaliplatin (with or without anti-VEGF antibody therapy) \- For patients with RAS and BRAF wild-type tumors: prior treatment with anti-EGFR monoclonal antibody (cetuximab or panitumumab) \- For patients with BRAF V600E mutation: prior treatment with a BRAF inhibitor (encorafenib) \*For patients who relapse during adjuvant chemotherapy or within 6 months after the last dose of postoperative adjuvant chemotherapy, that adjuvant therapy counts as prior systemic therapy. 4. Presence of measurable disease according to RECIST version 1.1. 5. Age ≥ 18 years at the time of informed consent. 6. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Laboratory values within 14 days prior to enrollment meeting all of the following (tests performed on the same weekday 2 weeks before the enrollment date are acceptable): <!-- --> 1. Absolute neutrophil count ≥ 1,500/mm³ 2. Hemoglobin ≥ 9.0 g/dL 3. Platelet count ≥ 75,000/mm³ 4. Total bilirubin ≤ 1.5 × institutional upper limit of normal (ULN) 5. AST (GOT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present 6. ALT (GPT) ≤ 2.5 × ULN; ≤ 5 × ULN if liver metastases are present 7. Creatinine ≤ 1.5 mg/dL 8. Proteinuria ≤ 1+ or \< 1.0 g/24 h (urine protein-to-creatinine ratio \< 1 may be used; if 24-hour urine is collected, the measured value takes precedence) 8. No blood transfusion within 7 days prior to enrollment (a transfusion given on the same weekday 1 week earlier is considered ineligible). 9\. Women of childbearing potential must have a negative pregnancy test within 14 days prior to enrollment. Both male and female participants must agree to use appropriate contraception during the study and for 4 months after the last dose of study treatment. Female participants must also agree not to breastfeed during the study and for 4 months after the last dose. (Tests performed on the same weekday 2 weeks before the enrollment date are acceptable.) 10. Able to take oral medication. 11. Written informed consent obtained from the participant. Exclusion Criteria: 1. Prior treatment with fruquintinib for metastatic colorectal cancer. 2. Prior treatment with any anti-CCR8 antibody, regardless of indication. 3. Receipt of chemotherapy, radiotherapy, immunotherapy, or any antitumor therapy, or investigational agents within 14 days prior to enrollment, or persistence of CTCAE Grade ≥ 2 toxicities from prior therapies (excluding alopecia, hyperpigmentation, and peripheral sensory neuropathy). 4. History of acute coronary syndrome (including myocardial infarction or unstable angina), coronary angioplasty, or stent placement within 6 months prior to enrollment. 5. History or current findings of congestive heart failure of NYHA Class III or higher. 6. Uncontrolled hypertension. 7. Known central nervous system metastases. (If CNS metastasis is clinically suspected, brain CT or MRI must be performed during screening.) 8. Active double primary malignancy (simultaneous or metachronous with disease-free interval \< 2 years), except for carcinoma in situ or intramucosal carcinoma lesions considered curable by local therapy. 9. Serious comorbidities requiring inpatient treatment (e.g., paralytic ileus, bowel obstruction, pulmonary fibrosis, uncontrolled diabetes, heart failure, myocardial infarction, angina, renal failure, hepatic failure, psychiatric disorders, cerebrovascular disorders, or transfusion-requiring ulcers). 10. Active infections, including: \- HBs antigen positive * Patients may be eligible if receiving nucleoside analog antiviral therapy and HBV-DNA \< 20 IU/mL (1.3 log IU/mL). \- HBs antibody positive or HBc antibody positive AND HBV-DNA positive * If HBV-DNA \< 20 IU/mL, the patient may be eligible. - HCV antibody positive * Patients may be eligible if HCV-RNA is below the detection limit. - HIV positive * Patients may be eligible if HIV infection is ruled out by confirmatory testing. * Other active infections requiring treatment. 11. History of autoimmune disease or chronic/recurrent autoimmune disease (patients with type 1 diabetes, hypothyroidism manageable with hormone replacement, or localized skin diseases such as vitiligo, psoriasis, or alopecia not requiring systemic therapy are eligible). 12. Requirement for systemic corticosteroids or immunosuppressive agents, or receipt of such therapy within 2 weeks prior to enrollment (treatment given on the same weekday 2 weeks earlier renders the patient ineligible), except for temporary administration for testing, allergic reactions, or edema associated with radiotherapy. 13. Lack of willingness or inability to comply with study procedures. 14. Considered unsuitable for the study by the principal investigator or sub-investigator. Pregnancy and Contraception: A woman of childbearing potential includes any female who has experienced menarche, has not undergone permanent sterilization (e.g., hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), and is not postmenopausal. Postmenopause is defined as at least 12 consecutive months of amenorrhea without another medical cause. Women using oral contraceptives, intrauterine devices, or mechanical barrier methods are considered capable of becoming pregnant. If a female participant is determined to be not capable of becoming pregnant, this must be documented in source records. Women must use effective contraception for at least 1 month prior to first study treatment, from the time of consent, and for at least 4 months after the last dose. Men must use effective contraception during study treatment and for at least 4 months after the last dose. Acceptable contraception includes vasectomy or condom use for male participants or male partners, and tubal ligation, contraceptive pessary, intrauterine devices, or oral contraceptives for female participants or female partners.