This clinical trial was designed to evaluate the safety and efficacy of Y90-SIRT combined with nivolumab, ipilimumab, and lenvatinib in patients with unresectable HCC. In addition to assessing short-term efficacy endpoints, such as ORR and PFS, this trial places particular emphasis on the OS benefit for patients. This study is therefore both novel and innovative.

Inclusion Criteria:

1. HCC confirmed as unresectable by imaging or histology, or patients who refuse surgery. Eligible for Y90-SIRT, with no evidence of extrahepatic disease on any available imaging. Lymph node involvement is permitted. The term "unresectable hepatocellular carcinoma" refers to a clinical state in which radical surgical resection is precluded because the tumor extent or an inadequate anticipated future liver remnant would prevent R0 removal, or because the procedural risk is prohibitively high, and where surgical intervention is not expected to yield a survival advantage over non-surgical therapies.
2. Aged between 18 and 80 years at the time of enrollment
3. Participants with Child-Pugh class A.
4. Participants with an ECOG performance status of 0 or 1 at the time of enrollment
5. Participants with a lung dose threshold of 30 Gy for yttrium-90 microspheres (each treatment dose ≤ 30 Gy), and an anticipated future liver remnant volume (FLRV) ≥ 30% of the total liver volume.
6. Participants with one or more measurable lesions; for those with segmental or right anterior/posterior portal vein invasion (Vp1/Vp2), the disease is confined to a single lobe and suitable for Y90 microsphere treatment.
7. If the patient is co-infected with hepatitis B virus (HBV) or hepatitis C virus (HCV), the following criteria must be met: HBV or HCV viral levels should be monitored during study participation. Patients with detectable hepatitis B surface antigen (HBsAg) or HBV DNA should have HBV DNA < 100 IU/ml and be managed according to local treatment guidelines. Most patients with advanced HCC and HCV have not received treatment for HCV infection. However, if antiviral therapy has been completed prior to the first administration of study drugs, these patients are considered eligible for inclusion.
8. No prior systemic therapy or transarterial radioembolization (Y90 glass microsphere TARE).
9. No active autoimmune disease and no history of chronic or recurrent autoimmune disease.
10. Adequate hematological, liver, and renal function as follows: (1) Absolute neutrophil count ≥ 1,500/mm³ (2) Hemoglobin level ≥ 9.0 g/dL (3) Platelet count ≥ 75,000/mm³ (4) Total bilirubin ≤ 1.5 × ULN (5) AST ≤ 2.5 × ULN (6) ALT ≤ 2.5 × ULN (7) International normalized ratio (INR) ≤ 1.25 (8) Albumin ≥ 31 g/L (9) 24-hour urine collection creatinine clearance (CL) > 40 mL/min or calculated creatinine clearance (CL) > 40 mL/min.
11. Not pregnant and no intention to conceive before or during treatment.
12. Written informed consent from the patient.
13. Expected survival of at least 12 weeks.

Exclusion Criteria:

1. Diffuse HCC or presence of vascular invasion or extrahepatic spread, with the following exceptions: invasion of segmental portal vein or hepatic vein.
2. Patients with Child-Pugh class C cirrhosis.
3. Any contraindication to hepatic arterial embolization: Known hepatic arterial reflux; known portosystemic shunt; coagulopathy (platelet count < 50 × 109/L, INR > 1.5); renal failure/insufficiency requiring hemodialysis or peritoneal dialysis; known severe arteriosclerosis; complete thrombosis or complete invasion of the main portal vein.
4. History of heart disease: congestive heart failure > New York Heart Association (NYHA) class II; active coronary artery disease (CAD) (myocardial infarction ≥ 6 months prior to study initiation is permitted); arrhythmias that are difficult to control with antiarrhythmic drugs or require a pacemaker (NCI-CTCAE v5.0 > grade 2); uncontrolled hypertension; clinically significant gastrointestinal bleeding within 4 weeks prior to initiation of study drugs.
5. Thrombotic or embolic events, such as cerebrovascular accident (including transient ischemic attack), deep vein thrombosis, or pulmonary embolism, occurring within 6 months prior to the first administration of study drug, except for segmental portal vein thrombosis.
6. Receipt of systemic anticancer therapy, radiotherapy, endocrine therapy, immunotherapy, or other investigational drugs within 4 weeks prior to study initiation.
7. Current or prior use of immunosuppressive drugs within 28 days before the first administration of nivolumab or ipilimumab. Exceptions to this criterion include: intranasal, inhaled, topical steroids or local steroid injections (e.g., intra-articular injection); physiological doses of systemic corticosteroids not exceeding 10 mg/day of prednisone or equivalent; steroids used for the prevention of allergic reactions (e.g., premedication for CT scan).
8. Receipt of live attenuated vaccines within 30 days prior to the first administration of study drug (IP). Note: If the patient is enrolled, live vaccines should not be administered during the study drug treatment period and within 30 days after the last dose of the study drug.
9. Major surgery within 4 weeks prior to study initiation, and the patient must have recovered from the effects of major surgery.
10. Patients with a second primary malignancy, apart from adequately treated basal cell carcinoma of the skin or carcinoma in situ of the cervix, unless disease-free for more than 3 years.
11. Uncontrolled comorbidities, including but not limited to persistent or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina, arrhythmia, interstitial lung disease, severe chronic gastrointestinal disease associated with diarrhea, or psychiatric/social conditions that limit compliance with study requirements, significantly increase the risk of adverse events, or impair the patient's ability to provide written informed consent.
12. Active infections, including tuberculosis (clinical assessment including medical history, physical examination, and imaging, as well as tuberculosis testing according to local practice), hepatitis B (known positive HBV surface antigen [HBsAg]), and hepatitis C. Patients with past or resolved HBV infection (defined as presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are eligible. Patients who are HCV antibody-positive are eligible only if HCV RNA measured by PCR is negative.
13. History of allogeneic organ transplantation.
14. Psychiatric disorders or altered mental status that interfere with understanding the informed consent process and/or compliance with the study protocol.
15. Symptomatic brain metastases. If symptoms are present, imaging is required to confirm the absence of brain metastases.
16. Pregnant or breastfeeding women.
17. Immunocompromised patients, such as those known to be serologically positive for human immunodeficiency virus (HIV).
18. Active or previously documented autoimmune or inflammatory diseases (including inflammatory bowel disease [such as colitis or Crohn's disease], diverticulitis [excluding diverticulosis], systemic lupus erythematosus, sarcoidosis, or Wegener's granulomatosis [granulomatosis with polyangiitis], Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, among others).
19. Known allergy or hypersensitivity to any study drug or its components.
20. Currently participating in or previously participated in a study involving an investigational drug, or use of an investigational device within 4 weeks prior to the first administration of study treatment.