Inclusion Criteria
* Hepatocellular carcinoma proven on biopsy or confirmed by radiological hallmarks according to the American Association for the Study of Liver Diseases (AASLD) or the European Association for the Study of the Liver (EASL) guidelines.
* Age ≥18 years.
* Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
* Not suitable for curative-intent treatment (including radical hepatic resection, liver transplantation, or curative ablation) after evaluation by the hepatobiliary tumor MDT expert group. Specifically, any of the following conditions are met:
1. R0 resection is not feasible.
2. In participants without cirrhosis, the volume of normal liver parenchyma is less than 30% of the total liver volume; or in participants with cirrhosis, the volume of normal liver parenchyma is less than 40% of the total liver volume; or ICG-R15 \>15%.
3. BCLC stage B or C.
* No prior systemic anti-tumor treatment for hepatocellular carcinoma before the first dose.
* According to RECIST version 1.1, at least 1 measurable lesion, or a measurable lesion that has clearly progressed after local treatment.
* Participants with portal vein tumor thrombus (PVTT):
1. Chen's group A and B, or Cheng's type I-III, can be enrolled.
2. Cheng's type IV, defined as superior mesenteric vein tumor thrombus, cannot be enrolled.
* Participants with hepatic vein tumor thrombus:
1. VV1 and VV2 can be enrolled.
2. VV3, or Sakamoto type I (inferior vena cava tumor thrombus), can also be enrolled.
3. Sakamoto type II (inferior vena cava tumor thrombus extending above the diaphragm) or Sakamoto type III (inferior vena cava tumor thrombus reaching the right atrium) cannot be enrolled.
* Participants with oligometastases outside the liver can be enrolled. Oligometastases are defined as up to three metastatic lesions in a maximum of two organs, with the largest diameter ≤3 cm.
* Child-Pugh score ≤7.
* Adequate organ and bone marrow function within 7 days before enrollment:
1. Absolute neutrophil count ≥1.5×10\^9/L; platelet count ≥75×10\^9/L; hemoglobin ≥9.0 g/dL.
2. Total bilirubin ≤2× upper limit of normal (ULN); ALT and AST ≤5× ULN; serum albumin ≥28 g/L; alkaline phosphatase ≤5× ULN.
3. Serum creatinine ≤1.5× ULN or creatinine clearance ≥50 mL/min; urine protein \<2+; if urine protein ≥2+, 24-hour urinary protein must be \<1 g.
4. INR ≤2.3 or prothrombin time prolongation ≤6 seconds.
* Estimated life expectancy ≥12 weeks.
* Female participants of childbearing potential, or male participants whose partners are of childbearing potential, must agree to use effective contraception during study treatment and for 6 months after the last dose.
* Signed written informed consent and ability to comply with study visits and procedures.
Exclusion Criteria
* Histologically or cytologically confirmed fibrolamellar hepatocellular carcinoma, sarcomatoid hepatocellular carcinoma, cholangiocarcinoma, or mixed histology.
* History of hepatic encephalopathy or liver transplantation.
* Clinically symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage. Participants with only minimal radiologic effusion without symptoms may be enrolled.
* Acute or chronic active hepatitis B or C infection, with HBV DNA \>2000 IU/mL or 10\^4 copies/mL, HCV RNA \>10\^3 copies/mL, or co-positivity for HBsAg and anti-HCV antibody. Participants controlled to within these limits after antiviral therapy may be enrolled.
* Central nervous system metastases.
* History of esophageal or gastric variceal bleeding due to portal hypertension within 6 months before first dose, or high bleeding risk judged by the investigator.
* Any life-threatening bleeding event within 3 months before first dose.
* History of arterial or venous thromboembolic events within 6 months before first dose, including myocardial infarction, unstable angina, cerebrovascular accident, transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other serious thromboembolic events, except stabilized catheter-related thrombosis or superficial thrombosis.
* Continuous use of aspirin \>325 mg/day or other known platelet inhibitors for 10 days within 2 weeks before first dose.
* Uncontrolled hypertension despite optimal treatment, defined as systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg, or history of hypertensive crisis or hypertensive encephalopathy.
* Toxicities from previous treatment not recovered to grade 0 or 1 per NCI-CTCAE version 5.0, except alopecia or clinically insignificant asymptomatic laboratory abnormalities.
* Symptomatic congestive heart failure (NYHA class II-IV) or left ventricular ejection fraction \<50%.
* Symptomatic or poorly controlled arrhythmia, history of congenital long QT syndrome, or screening QTc \>500 ms by Fridericia formula.
* Severe bleeding tendency, coagulation disorder, or current thrombolytic therapy.
* Gastrointestinal perforation or fistula, intestinal obstruction, extensive bowel resection with chronic diarrhea, Crohn's disease, ulcerative colitis, or chronic diarrhea within 6 months before first dose.
* Radiotherapy within 3 weeks before first dose, unless all radiation-related toxicities have resolved and there is no need for corticosteroids.
* Pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-related pneumonia, severe pulmonary dysfunction, or other severe lung disease.
* Active pulmonary tuberculosis, current anti-tuberculosis treatment, or anti-tuberculosis treatment within 1 year before first dose.
* HIV infection or known syphilis requiring treatment.
* Active or clinically uncontrolled severe infection within 4 weeks before first dose.
* Active autoimmune disease requiring systemic treatment within 2 years before first dose, except replacement therapy.
* Use of immunosuppressive drugs within 4 weeks before first dose, except local or physiologic-dose corticosteroids and temporary corticosteroids for allergy or airway symptoms.
* Live attenuated vaccine within 4 weeks before first dose or planned during the study period.
* Major surgery or unhealed wound, ulcer, or fracture within 4 weeks before first dose.
* Local treatment for hepatocellular carcinoma within 4 weeks before first dose. Traditional Chinese medicine with anti-tumor indications, or immunomodulatory drugs such as thymosin, interferon, or interleukin, within 2 weeks before first dose.
* Other acute or chronic diseases, psychiatric disorders, or laboratory abnormalities that, in the investigator's judgment, increase risk or interfere with study interpretation.
* Other malignancy diagnosed within 5 years before first dose, except radically treated basal cell carcinoma, squamous cell carcinoma of the skin, or carcinoma in situ.
* Prior treatment with anti-PD-1, anti-PD-L1/L2, anti-CTLA-4, or other immunotherapy, or prior targeted therapy against VEGF/VEGFR, RAF, MEK, PDGFR, FGFR, or related pathways.
* Known allergy to oxaliplatin, fluorouracil, leucovorin, lenvatinib, cadonilimab, or severe prior allergic reaction to other monoclonal antibodies.
* Aortic dissection aneurysm, celiac trunk dissection aneurysm, or superior mesenteric artery dissection aneurysm.
* Participation in another clinical trial within 4 weeks before first dose.
* Pregnancy or breastfeeding.
* Systemic multiple metastases, portal vein tumor thrombus involving the superior mesenteric vein, or inferior vena cava tumor thrombus extending above the diaphragm or reaching the right atrium.
* Any other condition that, in the investigator's judgment, makes the participant unsuitable for the study.
