Biomarker and Mechanism Study of Systemic Therapy in Unresectable HCC

Prior treatment

• Previous or concurrent other malignant tumors, except for adequately treated non-melanoma skin cancer, carcinoma in situ of the cervix, and papillary thyroid carcinoma.
• History of organ transplantation or hepatic encephalopathy. Known allergy to the selected targeted therapy drugs or immunotherapy drugs or drug excipients, or previous severe allergic reactions to other monoclonal antibodies.
• Active autoimmune disease requiring systemic treatment (e.g., disease-modifying drugs, corticosteroids, or immunosuppressants) within 2 years prior to the first dose (replacement therapies like thyroxine, insulin, or physiologic corticosteroids for adrenal/pituitary insufficiency are allowed).
• Diagnosed with severe (G3) varices by digestive endoscopy within 3 months prior to the first dose, or assessed by the investigator as having a high risk of bleeding. Subjects requiring withdrawal of informed consent.

Other illness

• Pathological diagnosis of mixed liver cancer, fibrolamellar hepatocellular carcinoma, or other non-hepatocellular malignant tumor components.
• History of gastrointestinal perforation and/or fistula within the past 6 months, history of intestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), extensive intestinal resection (partial colon resection or extensive small bowel resection complicated by chronic diarrhea), Crohn's disease, ulcerative colitis, or long-term chronic diarrhea.
• Known history of primary immunodeficiency disease. Uncontrolled hypertension (systolic blood pressure \> 140 mmHg or diastolic blood pressure \> 90 mmHg after optimal medical treatment), history of hypertensive crisis, or hypertensive encephalopathy.
• History of esophageal or gastric variceal bleeding events caused by portal hypertension within the past 6 months.
• Other conditions considered unsuitable by the investigator for participation in this clinical trial.

• Histologically or cytologically confirmed hepatocellular carcinoma (HCC), or meeting the clinical diagnostic criteria of the "Guidelines for Diagnosis and Treatment of Primary Liver Cancer (2024 Edition)" issued by the National Health Commission of China.
• Assessed by the investigator as unsuitable for surgical resection, or having intermediate to advanced stage HCC. Intermediate to advanced HCC is defined as Barcelona Clinic Liver Cancer (BCLC) stage B/C or China Liver Cancer (CNLC) stage IIa/IIb/IIIa/IIIb.
• Child-Pugh liver function class A or a score of 7. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 to 2.
• Willing to receive targeted therapy combined with immunotherapy or dual immunotherapy, and signed the informed consent form (applicable to the prospective cohort).
• Adequate bone marrow and organ function, meeting the following laboratory indicators: Absolute neutrophil count (ANC) \>= 1.0x10\^9/L without the use of granulocyte colony-stimulating factor within the past 14 days; Platelets \>= 50x10\^9/L without blood transfusion within the past 14 days; Hemoglobin \>= 90g/L without blood transfusion or erythropoietin use within the past 14 days; Total bilirubin \<= 3 x upper limit of normal (ULN); Albumin \>= 28g/L without human serum albumin or plasma infusion within the past 14 days; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<= 5 x ULN; Serum creatinine \<= 1.5 x ULN; Good coagulation function, defined as an international normalized ratio (INR) of prothrombin time \<= 1.5 x ULN.
• Subjects at risk of pregnancy (male or female) must use a contraceptive method with an annual failure rate of less than 1% during the entire treatment period and until 120 days after the last dose of the study drug (or 180 days after the last dose of chemotherapy drugs).