Safety and Efficacy of Folic Acid Combined With Atezolizumab and Bevacizumab as First-Line Therapy for Unresectable Hepatocellular Carcinoma

Inclusion Criteria:

* Age 18 to 75 years, male or female, and willing to provide written informed consent.
* Hepatocellular carcinoma (HCC) confirmed by histologic/cytologic examination or diagnosed according to accepted guideline-based clinical criteria.
* Unresectable HCC as determined by multidisciplinary evaluation; BCLC stage B disease that is unsuitable for, declined, or has progressed after locoregional treatment, or BCLC stage C disease; candidate for first-line systemic therapy.
* No prior systemic anticancer therapy for unresectable HCC. Prior locoregional treatment must have been completed at least 4 weeks before the first study treatment, with treatment-related toxicities recovered to Grade ≤1 or baseline.
* At least one measurable lesion according to RECIST version 1.1. The measurable lesion must not have received prior locoregional treatment unless unequivocal radiologic progression has subsequently occurred.
* Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and life expectancy of at least 12 weeks.
* Child-Pugh class A (score 5-6), without clinically decompensated ascites or hepatic encephalopathy.
* Adequate bone marrow function: absolute neutrophil count ≥1.5 × 10\^9/L, platelet count ≥75 × 10\^9/L, and hemoglobin ≥90 g/L.
* Adequate hepatic and renal function: total bilirubin ≤3 × upper limit of normal (ULN); AST and ALT ≤5 × ULN; albumin ≥28 g/L; INR ≤1.5; serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min.
* Urine protein dipstick ≤1+. If urine protein is ≥2+, 24-hour urinary protein must be \<1 g. Blood pressure must be adequately controlled at ≤150/90 mmHg.
* Upper gastrointestinal endoscopic evaluation within 6 months before the first study treatment. Intermediate- or high-risk gastroesophageal varices must have been appropriately managed and considered to have an acceptable bleeding risk by the investigator.
* Participants with positive HBsAg or detectable HBV DNA must receive appropriate antiviral therapy and have HBV DNA \<500 IU/mL before the first study treatment. HCV infection must be clinically stable.
* Serum vitamin B12 at or above the institutional lower limit of normal, with no uncorrected megaloblastic anemia or progressive unexplained neurologic symptoms.
* Participants of reproductive potential must agree to use highly effective contraception according to protocol requirements.

Exclusion Criteria:

* Prior treatment with PD-1, PD-L1, CTLA-4, or other immune checkpoint inhibitors, or prior bevacizumab treatment for HCC.
* Eligible for curative resection, ablation, or liver transplantation and willing to undergo such treatment.
* Active or recent clinically significant bleeding, including gastrointestinal bleeding, hemoptysis, or other Grade ≥2 bleeding within 6 months before the first study treatment, or untreated high-risk varices.
* Arterial thromboembolism, myocardial infarction, unstable angina, stroke/transient ischemic attack, severe arrhythmia, or NYHA class \>II heart failure within 6 months before the first study treatment.
* Tumor invasion of major blood vessels considered by the investigator to confer a significant near-term risk of fatal bleeding, or clinically significant risk of tumor rupture.
* Uncontrolled hypertension, clinically significant proteinuria, active peptic ulcer disease, high risk of gastrointestinal perforation or fistula, unhealed wound, or major surgery within 28 days before the first study treatment.
* Active autoimmune disease requiring systemic treatment, or systemic corticosteroid therapy equivalent to prednisone \>10 mg/day or other immunosuppressive therapy within 14 days before the first study treatment, except physiologic replacement therapy.
* Prior solid-organ transplantation or allogeneic hematopoietic stem-cell transplantation.
* Active severe infection, including uncontrolled HBV or HCV infection, active tuberculosis, or HIV infection associated with clinically significant immunodeficiency.
* Symptomatic, untreated, or unstable central nervous system metastases.
* Vitamin B12 deficiency, pernicious anemia, folic acid hypersensitivity, or continuous use of folic acid \>0.4 mg/day within 14 days before screening that cannot be discontinued.
* Current use of methotrexate or other antifolate drugs, or use of phenytoin, phenobarbital, or primidone that cannot be replaced or appropriately monitored.
* Pregnancy or breastfeeding; serious concurrent disease, psychiatric or cognitive disorder, or compliance issue that could interfere with study participation.
* Participation in another interventional clinical study within 4 weeks before the first study treatment, or any other condition considered by the investigator to make the participant unsuitable for enrollment.