This study plans to observe the changes of liver cancer and immune cell subsets by replicating the high abundance intestinal flora and liver cancer mouse model, reveal the relationship and mechanism of intestinal flora in the immunotherapy of liver cancer, and study the impact on prognosis by regulating the positive correlation of lactic acid bacteria and bifidobacteria of rumen coccus in patients with advanced liver cancer receiving immunotherapy

Select patients with advanced hepatocellular carcinoma who have been clinically consulted by MDT,those patients will be treated with carrilizumab and apatinib mesylate, and divide them into two groups randomly .Collect the stool specimens and clinical data from those who will be treated with oral bifidobacterium or without bifidobacterium during immunotherapy.; Use 16S sequencing to detect the changes in the composition ratio of intestinal flora and the level of galactose acid, judge the response to clinical treatment and establish the relationship curve with clinical treatment efficacy.

Inclusion Criteria:

1. Patients with HCC diagnosed by pathological histology or cytology or clinically confirmed.

2. Expected survival ≥ 12 weeks.

3. No systemic systemic antitumor therapy against hepatocellular carcinoma prior to the first dose.

4. Child-Pugh liver function rating: Grade A or B (≤7 points).

5. Stage IIIa: regardless of tumor status, with vascular invasion, no extrahepatic metastasis; liver function grade Child-Pugh A/B; PS 0~2, IIIb: regardless of tumor status, regardless of vascular invasion, with extrahepatic metastasis; liver function grade Child-Pugh A/B; PS 0~2. Not Stage B not suitable for radical surgery and/or local treatment.

6. ECOG physical status score ≤2.

7. At least one measurable lesion according to RECIST v1.1 (measurable lesion spiral CT tracing length ≥ 10 mm or enlarged lymph node short diameter ≥ 15 mm)

8. Routine blood tests: (no blood transfusion, G-CSF medication correction within 14 days prior to screening)

9. Laboratory test values within 7 days prior to enrollment meet the following requirements (no blood components, cell growth factors, albumin, or other corrective therapies are allowed within the first 14 days of obtaining laboratory tests), as follows.

   ① Blood count: absolute neutrophil count (ANC) ≥ 1.5×109/L; platelet count (PLT) ≥ 75×109/L; hemoglobin level (HGB) ≥ 9.0 g/dL.

   ② Liver function: serum total bilirubin (TBIL) ≤2× upper limit of normal (ULN); alanine amino transferase (ALT) and aspartate aminotransferase (ST) ≤5×ULN; serum albumin ≥28 g/L; alkaline phosphatase (ALP) ≤5×ULN.

   (iii) Renal function: serum creatinine (Cr) ≤ 1.5×ULN or creatinine clearance (CCr) ≥ 50 mL/min (Cockcroft-Gault formula); urine routine results show urine protein <2+; for patients with urine protein ≥2+ at baseline, 24-hour urine collection and 24-hour urine protein quantification <1g should be performed.

   ④ Coagulation: International normalized ratio (INR) and activated partial thromboplastin time (APTT) ≤ 1.5 times ULN.

10. Female patients of childbearing age or male patients whose sexual partners are women of childbearing age are required to use effective contraception throughout the treatment period and for 6 months after the last dose.

11. Sign a written informed consent form and be able to comply with protocol visits and related procedures.

Exclusion Criteria:

1. Patients with hepatocellular carcinoma who have received prior treatment with carrilizumab or any other PD-L1 or PD-1 antagonist, or who have participated in a phase III study with apatinib after receiving systemic therapy.
2. Subjects with any active autoimmune disease or history of autoimmune disease, including but not limited to: hepatitis, pneumonia, uveitis, colitis (inflammatory bowel disease), pituitary inflammation, vasculitis, nephritis, hyperthyroidism and hypothyroidism, except vitiligo or resolved childhood asthma/atopic disease. Patients with asthma requiring intermittent use of bronchodilators or other medical interventions should also be excluded.
3. Subjects with systemic or absorbable topical corticosteroids requiring immunosuppressive drugs or immunosuppressive doses. Prednisone or equivalent doses greater than 10 mg/day are contraindicated for 2 weeks prior to dosing. Corticosteroids for intravenous contrast allergy prophylaxis are permitted.
4. Persons with known or suspected allergic reactions to any component of the Karelixu formulation.
5. Central nervous system (CNS) metastases with clinical signs (including cerebral edema, steroid requirements, or progressive disease). Subjects receiving treatment for brain or meningeal metastases must be clinically stable (no evidence of new or enlarged metastases on magnetic resonance imaging [MRI] at least 4 weeks apart) and have discontinued treatment with systemic steroid immunosuppressive doses (>10 mg/day of prednisone or equivalent) at least 2 weeks prior to study drug.
6. Other malignancies (except cured basal cell carcinoma of the skin and cervical cancer)
7. Clinically significant cardiovascular disease, including but not limited to: severe acute myocardial infarction, unstable or severe angina, coronary artery bypass surgery, congestive heart failure (New York Heart Association (NYHA) class >2), ventricular arrhythmia requiring medical intervention, and left ventricular ejection fraction (LVEF) <50% within 6 months prior to enrollment.
8. Poorly controlled hypertension within 3 months: systolic blood pressure >140 mmHg, diastolic blood pressure >90 mmHg.
9. Subjects with bleeding tendency or on thrombolytic or anticoagulant therapy.
10. Subjects who have received systemic chemotherapy, radiotherapy, immunotherapy, hormonal therapy, surgery, or targeted therapy within 4 weeks (or equivalent to 5 half-lives, whichever is greater) prior to dosing or have any unresolved adverse event > Common Terminology Criteria for Adverse Events (CTCAE) Level 1 (allowing for unresolved stable chronic toxicity).
11. Subjects with clinically symptomatic ascites or pleural effusion that remains uncontrolled by therapeutic puncture and drainage.
12. History of gastrointestinal bleeding within 3 months or significant tendency to gastrointestinal bleeding such as: esophageal varices, locally active ulcerative lesions, gastric and duodenal ulcers, ulcerative colitis or gastrointestinal diseases such as portal hypertension or tumor resection with risk of bleeding
13. Severe bleeding (bleeding >30 ml within 3 months), hemoptysis (>5 ml within 4 weeks) or thromboembolic events (within 12 months, including stroke events and/or transient ischemic attacks).
14. Active infection or fever of unknown origin >38.5°C during the screening visit or on the first scheduled dosing date (patients with fever due to tumor may be included at the discretion of the investigator)
15. History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonia, drug-related pneumonia, or severely impaired lung function.
16. History of immunodeficiency including human immunodeficiency virus (HIV) positive, or other acquired or congenital immunodeficiency disease, or active hepatitis (transaminases not meeting inclusion criteria, hepatitis B virus (HBV) DNA ≥ 104/ml or hepatitis C virus (HCV) RNA ≥ 103/ml (or higher). Chronic hepatitis B virus carriers with HBV DNA <2000 IU/ml (<104/ml) must receive antiviral therapy throughout the study.
17. Subjects who have participated in other clinical trials or completed other clinical trials within 4 weeks.
18. Subjects who may be receiving other anti-tumor systemic therapy during the study.
19. Subjects who may have received a vaccine during the study period or who have previously received a vaccine within 4 weeks.
20. History of psychiatric disorder or psychotropic substance abuse.
21. Any other medical, psychiatric or social condition that, in the opinion of the investigator, may affect the subject's rights, safety, welfare or ability to sign informed consent, cooperate and participate in the study or interfere with the interpretation of the results.