This is an open-label, multicenter, randomized controlled Phase II trial. Patients with advanced hepatocellular carcinoma (HCC) who developed secondary resistance to first-line targeted-immunotherapy were randomly assigned to receive either the original first-line targeted-immunotherapy combined with FMT and PULSAR (experimental group), or second-line targeted-immunotherapy (control group). The first-line targeted-immunotherapy regimens consisted of tislelizumab combined with one of the first-line evidence-based tyrosine kinase inhibitors (TKIs), including lenvatinib, donafenib, apatinib, and sorafenib. Given that this study enrolled patients who progressed after an initial response to first-line targeted-immunotherapy, the second-line regimen in the control group continued tislelizumab immunotherapy while switching the TKI to regorafenib, an agent with second-line evidence.

Based on previous studies, the investigators aim to further explore the difference in efficacy between continuing the original targeted-immunotherapy regimen combined with FMT and PULSAR, versus standard second-line therapy, in patients with acquired resistance who experienced disease progression (PD) after achieving disease control (CR, PR or SD) with first-line targeted-immunotherapy.

The investigators will investigate whether fecal microbiota transplantation reshapes the tumor immune microenvironment by altering gut microbiota composition, and whether it can enhance immunogenicity and reverse the efficacy of immunotherapy plus TKI treatment when combined with radiotherapy. The investigators will also explore the immune-activating effect and synergistic mechanism of the PULSAR radiotherapy modality.

Primary Objective: Progression-Free Survival (PFS); Secondary Objectives: Overall Survival (OS), Objective Response Rate (ORR), Disease Control Rate (DCR), incidence and severity of Adverse Events (AE), changes in gut microbiota indices, and changes in tumor immune microenvironment indices.

Key Inclusion Criteria:

1. Clinically or pathologically confirmed unresectable primary hepatocellular carcinoma;
2. Liver cancer patients with BCLC stage B or C;
3. Not receiving systematic treatment before enrollment;
4. Patients with acquired resistance who achieved disease control (DCR: CR, PR, or SD) following first-line targeted-immunotherapy but later experienced disease progression (PD);
5. Child Pugh score ≤ 7 points;
6. Subject must have at least 1 measurable target lesion examined by CT or MRI according to RECIST1.1 criteria;
7. The Eastern Oncology Consortium (ECOG) Behavioral status score was 0 or 1.

Key Exclusion Criteria:

1. Failure to recover to NCI-CTC AE Grade ≤1 (excluding alopecia and fatigue) or to baseline level from toxicities and/or complications of prior interventions before PD-1 monoclonal antibody re-challenge;
2. Subjects requiring systemic therapy with corticosteroids (>10 mg prednisone equivalent daily) or other immunosuppressive agents within 14 days prior to PD-1 monoclonal antibody re-challenge；
3. Received abdominal radiotherapy or administered radioactive substances within 28 days prior to PD-1 monoclonal antibody re-challenge;
4. History of gastrointestinal perforation and/or fistula within 6 months prior to PD-1 monoclonal antibody re-challenge;
5. Active gastrointestinal bleeding within 1 week before the first fecal microbiota transplantation.
6. Occurrence of infection within 28 days prior to PD-1 monoclonal antibody re-challenge;
7. Active infection requiring systemic antimicrobial therapy before PD-1 monoclonal antibody re-challenge and intestinal microbiota transplantation, excluding local infections requiring only topical antibiotics (e.g., skin infections);
8. Received live or attenuated vaccines within 30 days prior to PD-1 monoclonal antibody re-challenge, or planned vaccination during the study period;
9. Known history of primary immunodeficiency or HIV infection;
10. Active or previously documented inflammatory bowel disease (e.g., Crohn's disease, ulcerative colitis, chronic diarrhea), except patients with chronic diarrhea who had no recurrence within 2 years before enrollment;
11. Known history of active tuberculosis (TB)；
12. Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation;
13. Suffering from active, known or suspected autoimmune disease, or with a history of autoimmune disease;
14. History of cardiovascular or cerebrovascular events or accidents within 6 months;
15. Other conditions deemed by the investigator to be inappropriate for enrollment, including patients with hyperprogressive disease.