This is a single-center, single-arm study designed to evaluate the efficacy and safety of second-line treatment in patients with advanced colorectal cancer (those who have progressed on or are intolerant to first-line oxaliplatin-based regimens with or without targeted therapy) receiving Levofolinic Acid + 5-FU continuous infusion combined with irinotecan hydrochloride liposome ± cetuximab/bevacizumab. Approximately 30 patients will be enrolled.

Inclusion Criteria:

1. Male or female, aged 18-75 years.

2. Histologically or cytologically confirmed colorectal adenocarcinoma.

3. Unresectable, MSS-type metastatic colorectal cancer that has failed or is intolerant to first-line standard oxaliplatin plus fluoropyrimidine ± targeted therapy.

   • Failure definition: progression during or within 3 months after completing first-line oxaliplatin/fluoropyrimidine ± targeted therapy.
   • Adjuvant setting: progression/recurrence during or within 6 months of completing adjuvant oxaliplatin-based chemotherapy/chemoradiation counts as first-line failure.

4. At least one measurable lesion by RECIST 1.1.

5. ECOG performance status 0-1.

6. Expected survival ≥ 3 months.

7. Adequate organ function within 14 days before enrollment (no transfusion or growth-factor support):

   • Hematology: Hb ≥ 90 g/L; WBC ≥ 3.0 × 10⁹/L; ANC ≥ 1.5 × 10⁹/L; PLT ≥ 90 × 10⁹/L.
   • Coagulation: INR ≤ 1.5 × ULN; APTT ≤ 1.5 × ULN (stable anticoagulation at therapeutic range allowed).
   • Renal: Creatinine clearance ≥ 50 mL/min (Cockcroft-Gault).
   • Hepatic:
   • No liver mets: TBIL ≤ 1.5 × ULN, ALT ≤ 2.5 × ULN, AST ≤ 2.5 × ULN.
   • Liver mets: TBIL ≤ 2 × ULN, ALT ≤ 5 × ULN, AST ≤ 5 × ULN.
   • Cardiac: LVEF ≥ 50 %.

8. Voluntary written informed consent; willing and able to comply with study procedures and follow-up.

9. WOCBP must have a negative serum/urine pregnancy test within 3 days before first study-dose (Cycle 1 Day 1).

10. All subjects (men and women) with reproductive potential must use a highly effective contraceptive method (annual failure rate < 1 %) from screening until 120 days after the last dose of investigational product or 180 days after the last chemotherapy dose, whichever is later.

Exclusion Criteria:

1. Prior exposure to topoisomerase-I inhibitors or their analogues in first-line therapy.

2. Documented hypersensitivity to any study drug or its excipients.

3. Pregnant or breast-feeding women.

4. Toxicities from prior therapy not resolved to CTCAE v5.0 Grade ≤ 1 (except alopecia or other toxicities deemed by the investigator to pose no safety risk).

5. Any anti-cancer therapy (chemotherapy, radiotherapy, biologics, targeted therapy, immunotherapy, etc.) within 4 weeks before first study-dose; major surgery (excluding biopsy) within 4 weeks that has not fully healed.

6. Severe psychiatric or psychological disorders that could compromise compliance.

7. Clinically significant cardiovascular disease:

   • Severe/unstable angina, symptomatic congestive heart failure (NYHA ≥ II), clinically significant arrhythmia requiring treatment, arterial thrombosis, acute coronary syndrome, MI, cerebrovascular accident (including TIA) or other Grade ≥ 3 CV event within 6 months prior to first dose.
   • QTcF ≥ 450 ms (men) or ≥ 470 ms (women) on resting 12-lead ECG.

8. Infection-related:

   • Active infection or unexplained fever > 38.5 °C on screening or dosing day (tumor fever allowed at investigator's discretion).
   • Serious infection (CTCAE Grade 3, e.g., pneumonia, bacteremia) requiring hospitalization within 4 weeks.
   • Active pulmonary inflammation on baseline imaging or need for systemic antibiotics (prophylactic antibiotics permitted).

9. Known HIV-positive, active hepatitis B, or hepatitis C:

   • HBsAg or HBcAb positive: HBV DNA must be ≤ 2.5 × 10³ copies/mL (or ≤ 500 IU/mL, or below LLoQ); HBsAg(+) subjects must receive anti-HBV prophylaxis throughout study treatment.
   • HCV-seropositive allowed only if HCV RNA negative (or below LLoQ).

10. History or current evidence of leptomeningeal metastases. Active brain metastases: untreated and/or symptomatic, or requiring corticosteroids or anticonvulsants. Subjects treated with surgery or radiotherapy may enter if imaging ≥ 4 weeks shows stable CNS disease, symptoms have resolved, no corticosteroids for ≥ 2 weeks, and acute toxicities have recovered.

11. Other severe uncontrolled disorders (e.g., frequent seizures, hepatic failure).

12. Other malignancies within 5 years, except adequately treated basal-cell carcinoma of skin or cervical carcinoma in situ.

13. Participation in another clinical drug trial within 4 weeks or less than 5 half-lives of the previous investigational agent, whichever is longer.

14. Any social or medical condition that, in the investigator's opinion, could interfere with informed consent, study participation, or interpretation of results.

15. Patients deemed by the investigator to be unsuitable for enrollment.