FAD Subtype-Guided Combination Therapy for Unresectable Hepatocellular Carcinoma

Inclusion Criteria:

1. Adults ≥18 years of age who voluntarily agree to participate and sign informed consent.
2. Histologically or cytologically confirmed hepatocellular carcinoma (HCC).
3. Unresectable or not suitable for curative local therapy, or progression after prior surgery or local therapy.
4. BCLC stage B or C.
5. No prior systemic therapy for HCC.
6. At least one measurable lesion according to RECIST v1.1.
7. Availability of fresh or archival tumor tissue for FAD subtype testing; if not available at screening, MRI fat fraction may be used temporarily.
8. Child-Pugh class A or B (≤7 points).
9. ECOG performance status 0-1.
10. Adequate organ function, including:

    * ANC ≥1.5 × 10⁹/L
    * Platelets ≥75 × 10⁹/L
    * Hemoglobin ≥90 g/L
    * Albumin ≥30 g/L
    * Total bilirubin ≤1.5 × ULN
    * ALT and AST ≤3 × ULN
    * Serum creatinine ≤1.5 × ULN or creatinine clearance \>50 mL/min
    * INR ≤1.2 or PT within 2 seconds above ULN
    * Urine protein \<2+ or 24-hour urine protein \<1.0 g
11. Controlled HBV infection (HBV-DNA \<2000 IU/mL; if above this level, ≥1 week of antiviral therapy with ≥1-log reduction prior to first dose). HCV-positive individuals must be managed per clinical guidelines.
12. Life expectancy ≥12 weeks.
13. Women of childbearing potential must have a negative pregnancy test; participants of reproductive potential must agree to effective contraception during treatment and for 6 months afterward.

Exclusion Criteria:

1. Non-HCC primary liver cancers (e.g., cholangiocarcinoma, combined HCC-CCA).
2. F3 subtype without liver lesions on imaging.
3. Clinically significant ascites requiring therapeutic intervention, or uncontrolled pleural/pericardial effusion.
4. Interstitial lung disease, pneumonitis requiring steroids, or active pulmonary infection.
5. Active or history of autoimmune disease requiring systemic treatment (exceptions allowed per protocol, e.g., controlled hypothyroidism).
6. Recent use (within 2 weeks) of systemic immunosuppressive therapy \>10 mg/day prednisone equivalent.
7. Gastrointestinal bleeding within 6 months, high-risk varices, active ulcers, fistula, perforation, or intra-abdominal abscess.
8. Known bleeding or clotting disorders; therapeutic anticoagulation not permitted.
9. Thromboembolic events within 6 months (e.g., stroke, PE).
10. Significant cardiovascular disease, including NYHA class ≥II heart failure, recent MI (within 1 year), unstable angina, clinically significant arrhythmias, or QTc prolongation.
11. Uncontrolled hypertension (SBP ≥140 mmHg or DBP ≥90 mmHg despite treatment), or history of hypertensive crisis.
12. Major vascular disease within 6 months (e.g., arterial thrombosis, aneurysm requiring repair).
13. Serious non-healing wounds, active ulcers, or fractures.
14. Inability to swallow oral medication or conditions affecting drug absorption.
15. Severe infection within 4 weeks, therapeutic antibiotics within 14 days, fever ≥38.5°C within 7 days before enrollment, or WBC \>15 × 10⁹/L.
16. Known HIV infection or other causes of immunodeficiency.
17. Receipt of live attenuated vaccines within 28 days before treatment.
18. Any condition that, in the investigator's judgment, would interfere with study participation or interpretation of results, including substance abuse, severe psychiatric illness, or social factors.