A Single-Arm, Multicenter, Exploratory Clinical Study of Transarterial Chemoembolization (TACE) Combined With Iparomlimab and Tuvonralimab Injection and Bevacizumab Injection for the Treatment of Unresectable, Non-Metastatic Hepatocellular Carcinoma (HCC)

Inclusion Criteria:

1. Voluntarily participate in the study and provide written informed consent.
2. Age 18-75 years, inclusive (male or female).
3. Histologically or cytologically confirmed HCC, or clinically diagnosed HCC according to the \*Clinical Practice Guidelines for Primary Liver Cancer (2024 Edition)\*.
4. Barcelona Clinic Liver Cancer (BCLC) Stage A, B, or C, not amenable to curative treatment (e.g., surgical resection, liver transplantation, or ablation).
5. At least one measurable lesion according to RECIST v1.1 criteria.
6. Suitable candidate for Transarterial Chemoembolization (TACE) with no known allergy or contraindication to iodized oil or epirubicin.
7. Child-Pugh Liver Function Class A.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
9. Life expectancy ≥ 3 months.
10. Adequate organ and bone marrow function.
11. If positive for Hepatitis B Virus (HBV) infection, HBV DNA must be \< 2000 IU/mL (\< 10,000 copies/mL if only copies/mL units available at the site) and the subject must be willing to receive continuous antiviral therapy throughout the study period. Subjects positive for Hepatitis C Virus (HCV) RNA must receive antiviral therapy according to clinical guidelines.
12. Subjects with esophageal/gastric varices must undergo evaluation and appropriate management prior to enrollment.
13. Women of childbearing potential (WOCBP): Must have a negative serum human chorionic gonadotropin (hCG) test within 7 days prior to initiation of study treatment; must be non-lactating; must agree to use highly effective contraception methods from signing informed consent until 120 days after the last dose of study treatment. A woman is considered of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥ 12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (hysterectomy, bilateral salpingectomy/oophorectomy). Male subjects with female partners of childbearing potential: Must agree to use highly effective contraception methods from signing informed consent until 120 days after the last dose of study treatment; must agree to refrain from sperm donation. Male subjects with pregnant partners must use condoms; no additional contraception is required.

Exclusion Criteria:

1. Known fibrolamellar HCC, sarcomatoid HCC, mixed hepatocellular cholangiocarcinoma, or cholangiocarcinoma; history of other active malignancies within 5 years or concurrently with HCC. Cured localized tumors (e.g., basal cell carcinoma, squamous cell carcinoma of the skin, superficial bladder carcinoma, carcinoma \*in situ\* of the prostate, cervix, or breast) are permitted.
2. Presence of Vp3 or Vp4 portal vein tumor thrombosis (PVTT), any grade of hepatic vein or inferior vena cava invasion; any grade of bile duct invasion. \*Note: Vp1 or Vp2 PVTT is permitted.\*
3. Presence of extrahepatic spread (EHS).
4. Intrahepatic lesion(s) with maximum diameter ≥ 10 cm, \> 10 intrahepatic lesions, or intrahepatic tumor burden ≥ 70% of liver volume, per RECIST v1.1.
5. Prior systemic anti-cancer therapy for HCC, including molecular targeted agents, cytotoxic chemotherapy, immunotherapy (e.g., immune checkpoint inhibitors, immune checkpoint agonists, cellular therapies), or biologic therapy (e.g., cancer vaccines, cytokines, growth factors).
6. Prior locoregional therapy for HCC, including therapeutic TACE, transarterial embolization (TAE), hepatic arterial infusion chemotherapy (HAIC), transarterial radioembolization (TARE).

1\) Prior curative surgery or ablation is permitted; one session of prophylactic TACE following curative resection is permitted.

2\) Prior percutaneous ethanol injection (PEI) or radiotherapy with curative intent is permitted.

7\. Prior or planned organ transplantation or allogeneic bone marrow transplantation.

8\. Current interstitial lung disease (ILD)/pneumonitis, history of ILD/pneumonitis requiring steroid treatment, or other pulmonary conditions that may interfere with the detection or management of immune-mediated pneumonitis (e.g., pulmonary fibrosis, organizing pneumonia \[e.g., bronchiolitis obliterans\], pneumoconiosis, drug-induced pneumonitis, idiopathic pneumonitis, or active pneumonia evidenced by screening chest computed tomography \[CT\] scan). Prior radiation pneumonitis within the radiation field is permitted. Active tuberculosis.

9\. Active autoimmune disease or history of autoimmune disease with potential for recurrence (e.g., autoimmune hepatitis, interstitial pneumonitis, uveitis, colitis, hypophysitis, vasculitis, nephritis, hyperthyroidism; subjects with hypothyroidism stable on hormone replacement are eligible). Conditions not requiring systemic therapy (e.g., vitiligo, psoriasis, alopecia), controlled Type I diabetes on insulin, or childhood asthma in complete remission without adult intervention are permitted. Asthma requiring bronchodilator therapy is excluded.

10\. Clinically significant ascites requiring therapeutic paracentesis or drainage (Child-Pugh score \>2 for ascites; asymptomatic ascites detected only radiographically is permitted); uncontrolled or moderate/large pleural effusion or pericardial effusion.

11\. Uncontrolled hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg based on ≥2 measurements) despite antihypertensive therapy; history of hypertensive crisis or hypertensive encephalopathy.

12\. Clinically significant cardiac disease. 13. History of spontaneous rupture of hepatic tumor(s). 14. History of hepatic encephalopathy. 15. History or presence of central nervous system metastases. 16. Congenital or acquired immunodeficiency (e.g., HIV infection). 17. Thromboembolic event within 3 months prior to treatment (e.g., cerebrovascular accident \[including transient ischemic attack, cerebral hemorrhage, cerebral infarction\], deep vein thrombosis, pulmonary embolism).

18\. History of gastrointestinal (GI) bleeding within 6 months prior to treatment or high risk of GI bleeding (e.g., high-risk or severe esophageal/gastric varices, active GI ulceration, persistent fecal occult blood positivity). \*Note: If fecal occult blood positive at baseline, repeat test; if persistently positive, esophagogastroduodenoscopy \[EGD\] required; exclusion if EGD shows varices/lesions with bleeding risk.\* 19. Abdominal fistula, GI perforation, intra-abdominal abscess, or bowel obstruction within 6 months prior to treatment.

20\. Major surgical procedure within 4 weeks prior to treatment or anticipated during study; unhealed wound, ulcer, or fracture within 4 weeks prior to treatment.

21\. Coagulopathy or bleeding diathesis (e.g., hemophilia); use of antiplatelet agents (e.g., aspirin \>325 mg/day, dipyridamole, ticlopidine, clopidogrel, cilostazol) or anticoagulants (e.g., warfarin, low molecular weight heparin) within 10 days prior to treatment.

22\. Significant vascular disease within 6 months prior to treatment (e.g., aortic aneurysm requiring surgical repair, recent peripheral arterial thrombosis).

23\. Severe infection within 4 weeks prior to treatment (e.g., requiring hospitalization for infection, bacteremia, or severe pneumonia complications); therapeutic antibiotics administered orally or intravenously within 2 weeks prior to treatment (prophylactic antibiotics, e.g., for UTI or COPD prevention, are permitted).

24\. Known hypersensitivity to the active substances or excipients of \*\*Iparomlimab and Tuvonralimab Injection\*\*, \*\*Bevacizumab Injection\*\*, or epirubicin; history of severe hypersensitivity to any other monoclonal antibody or anti-angiogenic targeted therapy.

25\. Use of immunosuppressive agents or systemic corticosteroids (\>10 mg/day prednisone or equivalent) for immunosuppressive purposes within 2 weeks prior to treatment.

26\. Administration of live attenuated vaccines within 4 weeks prior to treatment or planned during Iparomlimab and Tuvonralimab Injection treatment or within 60 days after the last dose.

27\. Treatment with any investigational agent within 4 weeks or 5 half-lives (whichever is longer) prior to treatment initiation.Subjects with any other condition deemed by the investigator to potentially affect study results or lead to premature study termination (e.g., alcoholism, drug abuse, other severe medical/psychiatric disorders requiring concomitant therapy, significant laboratory abnormalities, or familial/societal factors compromising subject safety).