The goal of this clinical trial is to explore the efficacy and safety of autologous iNKT cells in patients with progressed hepatocellular carcinoma (HCC) after treatment with PD-1 antibody. The main question it aims to answer are:

• the efficacy of autologous iNKT cells in patients with progressed HCC after treatment with PD-1 antibody.
• the safety of autologous iNKT cells in patients with progressed HCC after treatment with PD-1 antibody.

Participants will be randomized 1:1 to receive Regorafenib + PD-1 + iNKT cells (RPI group) or the treatment of Regorafenib + PD-1 (RP group).

Researchers will compare RPI group and RP group to see whether the iNKT cells can achieve a better therapeutic effect on HCC patients with PD-1 resistance.

Single center, randomized, open trial in Barcelona Clinic Liver Cancer（BCLC）C stage patients with progressed HCC after anti-angiogenic targeted drugs combined with PD-1 monoclonal antibody therapy to explore the efficacy and safety of autologous iNKT cells.

This study includes screening period, treatment period and follow-up period (until the subjects withdrew their informed consent or received other anti-tumor therapy or participated in other clinical trials or the researchers judged that it is not in the best interests of patients to continue to participate in the study) after treatment.

The patients will be randomized 1:1 using a random number table to receive Regorafenib + PD-1 + iNKT cells (RPI group) or the treatment of Regorafenib + PD-1 (RP group).

1. iNKT Cells：Intravenous infusion. The cells will be infused every two weeks as a course of treatment for up to six courses.
2. PD-1：Intravenous infusion, according to the drug instructions.
3. Regorafenib：Oral administration, according to the drug instructions. All target and non-target lesions will be assessed by chest, abdomen, and pelvis CT or MRI at baseline and every 8 weeks until radiological progression (according to mRECIST/iRECIST).

Safety and side-effect profiles will be assessed based on the nature, frequency, and severity of adverse events, according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.

Inclusion Criteria:

• 18-75 years of age.
• Barcelona Clinic Liver Cancer（BCLC） C stage hepatocellular carcinoma (HCC) confirmed by CT, MRI, and/or histopathology.
• Progressed after receiving anti-angiogenic targeted drugs combined with PD-1 monoclonal antibody.
• Life expectancy of at least 12 weeks.
• Child-Pugh A/B.
• Voluntary signing of informed consent.

Exclusion Criteria:

• History of severe hypertension or cardiac disease.
• known central nervous system (CNS) tumor or combined with other malignant disorders.
• Uncontrolled immune system or infectious disease.
• Known history of the human immunodeficiency virus (HIV) or syphilis infection.
• History of stem cell transplant or organ allograft.
• History of allergy to immunotherapy or related drugs.
• Bilirubin is twice times the upper limit of normal.
• Glomerular filtration rate （GFR）< 60ml/min.
• Serious complications include moderate or severe infective pleural and peritoneal effusion, pericardial effusion, upper gastrointestinal bleeding, hepatic encephalopathy.
• Pregnancy or lactation.
• History of severe allergy to any monoclonal antibody or anti-angiogenic targeted drug.
• Deemed not suitable for cellular immunotherapy by the investigators.

Block randomization was performed by the independent masked statistician. Two independent masked radiologist who are blinded to patients' clinical information will review the imaging examinations.