This study is a prospective, multicenter Phase II trial evaluating a personalized treatment strategy for patients with unresectable hepatocellular carcinoma (HCC). The study uses a metabolic classification system called the fatty acid degradation (FAD) subtype to guide therapy selection. Patients will be assigned to different treatment groups based on their tumor's FAD subtype, determined through RNA-seq analysis of the tumor tissue obtained from liver biopsy.

This prospective, multicenter Phase II study evaluates a precision-medicine treatment strategy for unresectable hepatocellular carcinoma (HCC) using a metabolic classification system based on fatty acid degradation (FAD). Prior translational research has shown that HCC exhibits heterogeneous metabolic phenotypes, and that tumors with distinct FAD signatures demonstrate different immune microenvironments and therapeutic sensitivities. Building on these findings, this study applies FAD subtype profiling in clinical practice to guide individualized treatment selection.

All enrolled patients will undergo tumor tissue analysis for transcriptomic assessment and FAD scoring. When tumor tissue is not immediately obtainable, MRI fat-fraction measurement may be used temporarily to facilitate enrollment, with tissue-based classification performed afterward. Based on the predefined FAD subtypes (F1, F2, and F3), patients will be allocated to tailored therapeutic strategies designed to align with each subtype's metabolic and microenvironmental characteristics.

Patients with F1 or F2 subtypes will receive systemic therapy with camrelizumab and apatinib, reflecting prior evidence that these subtypes may benefit from immunotherapy combined with anti-angiogenic therapy. Patients with the F3 subtype that characterized by enhanced lipid metabolic activity will receive TACE in addition to camrelizumab and apatinib.

Treatment is delivered in 3-week cycles, with imaging assessments performed regularly to evaluate tumor response. Safety will be closely monitored throughout the study, including immunotherapy-related toxicities, anti-angiogenic drug-associated events, and TACE-related complications. After discontinuation of study treatment, participants will enter a structured follow-up schedule to monitor survival and subsequent treatments.

In addition to evaluating clinical outcomes, the study incorporates exploratory biomarker analyses, including transcriptomics, metabolomics, and imaging-based fat quantification. These analyses aim to improve understanding of how metabolic subtypes influence therapeutic response and resistance mechanisms, and to assess whether MRI-based fat fraction can serve as a noninvasive surrogate for molecular FAD classification.

Overall, this study seeks to translate metabolic phenotyping into clinical decision-making and to determine whether FAD-guided personalized therapy can improve treatment outcomes for patients with unresectable HCC.

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.

Individual participant data (IPD) will not be shared. The study involves genomic, transcriptomic, and clinical imaging data that may pose risks to participant privacy, and data sharing is not planned.