Retlirafusp Alfa Plus Targeted Therapy and Chemotherapy for Unresectable Colorectal Liver-Limited Metastases

Inclusion Criteria:

1. Signed written informed consent before any trial-related procedure.
2. Age ≥18 and ≤79 years, male or female.
3. Histopathologically confirmed colorectal adenocarcinoma; liver metastasis confirmed by pathology or imaging.
4. No prior first-line systemic therapy (targeted, immunotherapy, systemic chemotherapy) specifically for liver metastases.
5. At least 1 measurable lesion per RECIST 1.1.
6. Multidisciplinary-team-confirmed initially unresectable colorectal liver metastases (cannot achieve R0/R1 resection; or predicted future remnant liver volume \< 30 %; or insufficient hepatic inflow/outflow). Patients with extra-hepatic metastases (excluding brain / bone metastases) amenable to local therapy are eligible.
7. Microsatellite-stable (MSS) / mismatch-repair-proficient (pMMR) confirmed by IHC or PCR.
8. ECOG Performance Status 0-1.
9. Expected survival ≥12 weeks.
10. No urgent-surgery indications (e.g., primary-tumor bleeding, obstruction).
11. Adequate organ function within 14 days prior to first study-drug:

    * ANC ≥1.5 × 10⁹/L; Platelets ≥75 × 10⁹/L; Hb \> 70 g/L
    * Total bilirubin ≤1.5 × ULN; Albumin ≥28.0 g/L
    * AST / ALT ≤5 × ULN
    * Creatinine ≤1.5 × ULN; Cockcroft-Gault creatinine clearance ≥60 mL/min
    * INR / PT ≤1.5 × ULN
12. Females of reproductive potential / males with reproductive-potential partners agree to highly-effective contraception starting 7 days prior first dose until 24 weeks after last dose.
13. Serum pregnancy test negative within 7 days before first dose (women of child-bearing potential).
14. Willing and able to comply with all trial visits, treatment and assessments.-

Exclusion Criteria:

* 1\. Inability to tolerate systemic chemotherapy or subsequent surgery. 2. Liver metastases occurring during or within 6 months after completion of oxaliplatin-based adjuvant chemotherapy for primary colorectal tumor.

  3\. Major surgery within 6 weeks before study entry; severe trauma / non-healing wounds / fractures.

  4\. Myocardial infarction, unstable angina, coronary-artery-bypass-graft within prior 3 months; NYHA class III-IV heart failure.

  5\. Prior treatment with immune-checkpoint-inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 etc.).

  6\. Concurrent or prior other malignancy whose expected survival is shorter than colorectal-liver-metastasis prognosis.

  7\. History of allogeneic hematopoietic-stem-cell or solid-organ transplant (except corneal transplant).

  8\. History of moderate-severe hypersensitivity / anaphylaxis to antibody-based therapeutics.

  9\. Clinically-significant bleeding diathesis or major bleeding episode within prior 3 months (e.g., gastrointestinal bleeding, esophageal varices, hematemesis, hemoptysis).

  10\. Symptomatic large-volume ascites / pleural effusion / pericardial effusion requiring intervention.

  11\. Primary-tumor perforation, abdominal infection occurring within prior 3 months without adequate management.

  12\. Known hypersensitivity to active ingredients or excipients of study drugs. 13. Active peptic ulcer, gastrointestinal obstruction, active GI bleeding, perforation, malabsorption, uncontrolled inflammatory bowel disease.

  14\. Pregnant or lactating women. 15. Concurrent participation in another interventional clinical trial. 16. Any other condition judged by investigator to make subject unsuitable for trial participation.