Gut Microbiota Modulation for Immunotherapy Resensitization in Advanced Renal Cell Carcinoma

Inclusion Criteria: * Pathological Diagnosis and Subtype Specification Histologically confirmed metastatic renal cell carcinoma (mRCC) of either clear cell type or non-clear cell type, with non-clear cell histologies restricted to papillary, chromophobe, or unclassified subtypes. Sarcomatoid features are allowed. Other non-clear cell subtypes, including but not limited to collecting duct carcinoma and renal medullary carcinoma, are excluded. Based on the pathological subtype, enrolled patients will be assigned to two cohorts: the primary cohort consists of patients with histologically confirmed metastatic clear cell RCC, and the exploratory cohort consists of those with histologically confirmed metastatic non-clear cell RCC (subtypes limited to papillary, chromophobe, or unclassified). * Immunotherapy Resistance Patients must have received at least two cycles of PD-1/PD-L1 ICI therapy and demonstrated disease progression either during treatment or within six months after the last dose. Progressive disease must be confirmed by the investigator according to RECIST 1.1 criteria, with additional radiographic confirmation performed within four weeks after the initial documented progression. * Prior Treatment Lines and Sequence Restriction Patients must have received no more than two prior lines of systemic therapy, with no more than one line consisting of a PD-1/PD-L1 ICI. This PD-1/PD-L1 ICI based therapy may have been administered as first-line or second-line treatment for advanced or metastatic RCC, or as neoadjuvant or adjuvant therapy. Furthermore, this line of therapy must be the most recent prior treatment line, meaning that no other anticancer therapy has been administered following its completion. * Lesion Requirement Patients must have at least one measurable lesion per RECIST v1.1, as assessed by the investigator or by local radiologic evaluation. * Pre-treatment Tumor Biopsy Quality The pre-treatment tumor biopsy specimen must contain viable tumor tissue accounting for at least 75% of the total examined area. * Prior Radiotherapy Washout Participants who have received palliative radiotherapy for non-central nervous system lesions must complete such therapy at least 2 weeks prior to the first dose of study treatment. Participants for whom the only measurable lesions reside within a previously irradiated field are eligible for enrollment, provided that such lesions have shown clear progression and remain accurately measurable. * Recovery from Prior Treatment Toxicity All toxicities from prior anticancer therapies must have recovered to baseline or to Grade ≤1 according to the CTCAE version 5.0, with the exception of controllable AEs such as hypothyroidism that are clinically insignificant or remain stable under supportive care. * General Baseline Status Patients must be ≥18 years of age, have an Eastern Cooperative Oncology Group (ECOG) performance status \<2, an American Society of Anesthesiologists (ASA) score ≤2, and a life expectancy ≥6 months. * Adequate Liver Function Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤3 × upper limit of normal (ULN), or ≤5 × ULN in patients with liver metastases. Total bilirubin ≤1.5 × ULN, except for patients with Gilbert's syndrome, in whom bilirubin ≤3.0 mg/dL is allowed. * Adequate Renal Function Creatinine clearance ≥30 mL/min (Cockcroft-Gault formula) or serum creatinine ≤1.5 × ULN, and urine protein-to-creatinine ratio ≤1 mg/mg. * Adequate Bone Marrow Function White blood cell count \>2.0 × 10⁹/L, absolute neutrophil count \>1.5 × 10⁹/L, platelet count \>100 × 10⁹/L, lymphocyte count ≥0.3 × 10⁹/L, and hemoglobin ≥90 g/L, with no blood transfusion within 14 days prior to assessment. * Viral Serology Patients must be negative for human immunodeficiency virus (HIV), negative for hepatitis B surface antigen (HBsAg), or positive for hepatitis B core antibody (HBcAb) with negative HBV DNA, and negative for hepatitis C antibody (HCV Ab), or positive with negative HCV RNA. * Informed Consent Patients must provide written informed consent. * Compliance Patients must be willing and able to adhere to the study protocol. Exclusion Criteria: \- Recent Microbiota Interference Patients are excluded if they have received systemic antibiotics within 4 weeks prior to screening, or have received any live bacterial preparations or commercial prebiotics within 2 weeks prior to screening, or are currently using or plan to use probiotics, yogurt, or foods supplemented with bacteria during the treatment period. \- Immune-Related Severe Toxicity or Autoimmune Status Patients are excluded if they meet any of the following criteria: * Have a history of permanent discontinuation of immunotherapy due to immune-mediated adverse events; * Have active or known autoimmune disease, except for type 1 diabetes mellitus, hypothyroidism requiring only hormone replacement therapy, and vitiligo; * Have an immunosuppressive status, defined as confirmed immunodeficiency, receipt of systemic corticosteroids at a dose equivalent to \>10 mg of prednisone per day or other immunosuppressive agents (excluding inhaled or topical corticosteroids), or a history of active autoimmune disease requiring systemic therapy within the past 2 years. \- Prior Specific Immunotherapy or Excessive Therapy Patients are excluded if they have received prior treatment with a CTLA-4 ICI or more than two prior systemic therapy regimens. \- Gastrointestinal Risk Factors Patients are excluded if they have a history of inflammatory bowel disease (including Crohn's disease or ulcerative colitis); chronic severe diarrhea; or grade ≥3 immune-related colitis; or present with gastrointestinal metastatic lesions; or have undergone major abdominal surgery that may impair intestinal absorption or peristaltic function. \- Oral Administration Barrier Patients are excluded if they have dysphagia or are unable to take the required oral study medication. \- Rapid Tumor Progression Patients are excluded if they have rapidly progressive disease such that, in the opinion of the investigator, they cannot safely tolerate a 4-week washout period and a 2-week reconditioning period. \- Active Interstitial Lung Disease or Pneumonitis Patients with active interstitial lung disease or pneumonitis, or a history of either condition requiring systemic steroid therapy, are excluded. \- Uncontrolled Brain Metastases or Central Nervous System Disease Patients with known brain metastases, cranial epidural disease, or significant vasogenic edema are excluded unless they have received adequate radiotherapy or surgery and have been stable for at least 4 weeks prior to the first dose of study treatment. \- Severe Cardiac Disease Patients are excluded if they have a history of myocarditis or congestive heart failure (New York Heart Association \[NYHA\] class III-IV), unstable angina, uncontrolled severe arrhythmia, or myocardial infarction within 6 months prior to enrollment. \- Recent Other Antineoplastic Treatment Patients are excluded if they have received, prior to the first dose of study treatment:any small molecule kinase inhibitor within 2 weeks; cytotoxic agents, biologics, or other systemic anticancer therapies within 4 weeks; radiotherapy for bone metastases within 2 weeks, or any other radiotherapy within 4 weeks. * Planned Other Antineoplastic Treatment Patients are excluded if they require any other systemic or local antineoplastic therapy during the study period, with the exception of bisphosphonates or denosumab for the management of bone metastases. * Active Second Malignancy Patients are excluded if they have a second active malignancy diagnosed within the preceding 2 years, with the exception of indolent or early-stage tumors, including non-melanoma skin cancer and carcinoma in situ. * Laboratory Abnormalities Patients are excluded if they meet any of the following criteria: * White blood cell count \<2.0 × 10⁹/L, absolute neutrophil count \<1.5 × 10⁹/L, or platelet count \<100 × 10⁹/L; * AST/ALT \>3 × ULN, or \>5 × ULN in patients with liver metastases, or total bilirubin \>1.5 × ULN (except for Gilbert's syndrome); ③Creatinine clearance \<30 mL/min or serum creatinine \>1.5 × ULN. * Other Uncontrolled Comorbidities Patients are excluded if they have any of the following: * Uncontrolled tumor-related pain, with painful lesions requiring palliative radiotherapy to be managed prior to enrollment; * Uncontrolled pleural effusion, pericardial effusion, or ascites requiring drainage more frequently than once per month, the presence of an indwelling catheter such as a PleurX® device is permitted; ③Moderate to severe hepatic impairment, defined as Child-Pugh class B or C; ④Uncontrolled or symptomatic hypercalcemia. * Other General Exclusions Patients are excluded if they meet any of the following criteria: * Have received prior allogeneic stem cell transplantation or solid organ transplantation; * Have active hepatitis B (HBV DNA positive), active hepatitis C (HCV RNA positive), or HIV infection; * Have undergone major surgery within 4 weeks prior to study treatment; * Have a history of allergy to food or antibiotics; ⑤Are pregnant, breastfeeding, or plan to conceive or father children during the study period (from pre-screening or screening visit until 120 days after the last dose); ⑥Require dialysis, have malabsorption syndrome, uncontrolled electrolyte disturbances, or require specific anticoagulants such as warfarin; ⑦Have any medical or psychological condition that may compromise safety or compliance.