Perioperative Trial With IO/TKI for Multi-stage Clear Cell Renal Cell Carcinoma

Inclusion Criteria: * Patients have fully understood and give written informed consent prior to receive neoadjuvant therapy. Patients with history of major psychiatric disease must be judged able to fully understand the trial, and the explicit consent of family members is required; * Patients with the ages range from 18 to 80 years old (at the time of signing informed consent); * Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1; * Patients have at least 1 measurable target lesion according to RECIST v1.1. The target lesion can be biopsied as per protocol. * Histologically confirmed clear cell RCC; * Patients will be enrolled into 3 separate cohorts based on their clinical TNM at the time of baseline screening: 1. Cohort 1: localized ccRCC (cT1-2N0M0): the primary tumor in this cohort must meet the subsequent criteria: * The cT1a primary tumor should have ≥10 R.E.N.A.L. score, or locate in renal hilum close to renal artery or its main branch; * Patients with cT1b-2b primary tumors can be directly enrolled; * In case of necessary, patients will undergo dual radiological examinations using contrast-enhanced CT and MRI to rule out potential invasion of the renal pelvis or perirenal fat as per protocol. 2. Cohort 2: locally advanced ccRCC (cT3-4N0M0 or cTanyN1M0); 3. Cohort 3: metastatic ccRCC (cTanyNanyM1): the patients should be evaluated as suitable for cytoreductive nephrectomy. * Patient have no symptomatic metastatic lesions requiring urgent intervention; * The sum of the diameters of the other target lesions (excluding the primary tumor) does not exceed the longest diameter of the primary tumor. * The patients who are treatment-naive, and have not received systemic therapy for any tumor; * Adequate main organ function. The screening laboratory indicators must meet the following criteria: 1. Hemoglobin ≥ 90 g/L (Without blood transfusion); 2. Platelets count ≥ 100 x 109/L; 3. Absolute neutrophil count ≥ 1.5 x 109/L; 4. Serum creatinine ≤ 1.5 x ULN, or eGFR \> 60 mL/min/1.73m2; 5. Total bilirubin ≤ 1.5 mg/dL; 6. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≤ 2.5 x ULN for patients without evidence of liver metastases; AST and/or ALT ≤ 5 x ULN for patients with liver metastases; 7. Normal CK; 8. Normal Troponin T; 9. Normal LDH. * Willingness and ability to comply with planned visits, therapeutic laboratory testing, and other procedures. Exclusion Criteria: * Signs of tumor metastasis involving the central nervous system, or radiological evidence of brain metastasis; * History of malignant tumors other than ccRCC within the previous 5 years, with the exception of malignant tumors that can be expected to be cured with treatment (including but not limited to adequately treated thyroid cancer, carcinoma in situ of the cervix, basal or squamous cell skin cancer, or ductal carcinoma in situ of the breast treated with radical surgery); * Prior to participating in the study, patients have received prior immune checkpoint inhibitors, investigational drugs or device therapy; * History of undergoing major surgery (judged by the investigator) within 4 weeks before the first trial dose, are recovering, or are unable to undergo baseline puncture; * History of severe drug allergy, including but not limited to antibody drugs; * Patients with contraindications to immunotherapy restart, including but not limited to: 1. Grade 2-4 immune myocarditis; 2. Severe grade 4 proteinuria; 3. Severe or life-threatening grade 4 immune hepatitis; 4. Severe grade 3-4 immune pneumonitis; 5. Severe inflammatory arthritis that significantly affects daily life or quality of life; 6. Severe neurological toxicity: 7. Myasthenia gravis grade 2-4; 8. Guillain-Barre syndrome (GBS) or transverse myelitis of any grade; 9. Grade 2-4 encephalitis; 10. Severe or life-threatening grade 3-4 pancreatitis; 11. Severe or life-threatening bullous disease (grade 3-4); 12. Severe grade 3-4 uveitis or episcleritis. * Known history of allogeneic organ transplantation or allogeneic hematopoietic stem cell transplantation or long-term corticosteroid therapy. * Non-resolution of toxicity after previous antineoplastic therapy, i.e., resolution to baseline, CTCAE v5.0 grade 0-1 (excluding alopecia), or inclusion/exclusion criteria. Irreversible toxicities (e.g., hearing loss) that would not reasonably be expected to be exacerbated by the study drug can be included in the study; * Known history of clinically significant liver disease, including active viral hepatitis (hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (HbcAb) positive, HBV DNA\>10000 copies /mL or \>2000 IU/mL; Hepatitis C virus (HCV) antibody positive and HCV RNA positive), or other active hepatitis, clinically significant moderate to severe cirrhosis; * Patients with uncontrolled third space effusion requiring repeated drainage, such as pleural effusion, ascites, pericardial effusion, etc. (Patients who do not need drainage of effusion or stop drainage for 3 days without significant increase in effusion can be enrolled); * Receiving a systemic corticosteroid (prednisone \> 10mg/ day or equivalent) or other immunosuppressive medication within 14 days before the first study medication; * Patients with any severe and/or uncontrolled disease, including: 1. Hypertension that is not well controlled by antihypertensive medication; 2. Unstable angina pectoris or myocardial infarction, coronary artery bypass grafting or stent implantation within 6 months before study medication; 3. Grade I or above myocardial ischemia or myocardial infarction, arrhythmia (including QTc≥480ms) and ≥ grade 2 congestive heart failure (New York Heart Association (NYHA) classification); Degree II or above heart block; Left ventricular ejection fraction (LVEF) \< 50%; 4. Poorly controlled diabetes (fasting blood glucose \> 10 mmol/L); 5. Patients with urinary protein ≥++ and confirmed 24-hour urinary protein \> 1.0g; 6. Severe active or uncontrolled infection. * Patients with or suspected to have active autoimmune diseases, including but not limited to systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, etc.; * Renal failure requiring hemodialysis or peritoneal dialysis; * Patients with a history of immunodeficiency, including HIV positive patients, other acquired immunodeficiency diseases, congenital immunodeficiency diseases, or organ transplantation history; * History of live attenuated vaccine inoculation within 4 weeks before the first study drug or the expected vaccination during the study period; * History of psychiatric drug abuse and can not quit or have a history of mental disorders; * Women who are of childbearing potential. Women of childbearing potential must have a negative serum or urine pregnancy test, and must use appropriate methods of contraception. * The presence of any other severe, acute or chronic medical disease or mental illness or laboratory abnormality, as judged by the investigator, that may increase the risk associated with participation in the study or that may interfere with the interpretation of the results of the study.