Inclusion Criteria:
1. Patients who have signed an informed consent form and are willing to complete the study according to the protocol;
2. Age between 18 and 75 years old;
3. Patients with metastatic or unresectable nccRCC who have been histologically or cytologically diagnosed (AJCC 8th edition staging);
4. At least one measurable lesion, as required by the "Measurable Lesion" criteria in RECIST 1.1;
5. Not treated with any systemic anti-tumor therapy since diagnosis, including chemotherapy, targeted therapy, and immunotherapy (including but not limited to anti-PD-1/PD-L1 antibodies, anti-CTLA-4 antibodies, etc.);
6. Expected survival of 3 months;
7. ECOG score 0-1;
8. Good organ function: meeting the following requirements:
1. Absolute neutrophil count (ANC) ≥1.5× 109/L;
2. Platelet count ≥100×109/L;
3. Hemoglobin ≥9g/dL;
4. Serum albumin ≥2.8g/dL;
5. Total bilirubin ≤1.5 ×ULN, ALT, AST, and/or ALP ≤3 ×ULN; if liver or bone metastasis is present, ALP ≤5 ×ULN;
6. Serum creatinine ≤1.5×ULN and creatinine clearance rate 60 mL/min (Cockcroft-Gault, see Appendix 3);
7. Activated partial thromboplastin time (APTT) and international normalized ratio (INR) ≤1.5× ULN (patients receiving stable doses of anticoagulant therapy such as low-molecular-weight heparin or warfarin and whose INR is within the expected therapeutic range of anticoagulants can be screened);
9. Patients infected with hepatitis B Virus (HBV) and inactive/asymptomatic carriers, or patients with chronic or active HBV will be allowed to enroll if their HBV DNA\<500 IU/mL (or 2500 copies/mL); HCV antibody-positive patients will be allowed to enroll if HCV-RNA is negative during screening.
Note: HBsAg-positive patients or patients with detectable HBV DNA who receive antiviral treatment should undergo treatment for \>2 weeks before enrollment, and continue treatment for 6 months after the study drug treatment.
10. \*For women of reproductive age, urine or serum pregnancy test results should be negative within 7 days or less before treatment. And use a medically approved contraceptive (such as an intrauterine device, contraceptive or condom) during the study treatment period and at least 3 months after the last use of Serplulimab and at least 6 months after the last use of chemotherapy;
11. Male subjects who are not sterilized must be willing to use a medically approved contraceptive method (such as an IUD, contraceptive or condom) for the duration of the study treatment, at least 3 months after the last use of Serplulimab and at least 6 months after the last use of chemotherapy.
Exclusion Criteria:
1. There is a history of allergy to any component of the drug SLT or the drug Fruquintinib.
2. A history of or concurrent malignancy (excluding skin basal cell carcinoma and cervical carcinoma in situ and papillary carcinoma of thyroid) that has been cured for more than 5 years and has no active cancer）.
3. Uncontrolled clinical symptoms or diseases of the heart, including: a) NYHA class II or above heart failure; b) unstable angina; c) myocardial infarction within 1 year; d) significant atrial or ventricular arrhythmias requiring clinical intervention.
4. Having received any of the following treatments: a) previous treatment with PD-1, PD-L1 antibodies, or CTLA-4 antibodies; b) received any investigational drugs within 4 weeks prior to the first dose of the study drug; c) enrolled in another clinical trial, unless it is an observational (non-interventional) study; d) requiring systemic treatment with corticosteroids (\>10 mg/day prednisone or equivalent) or other immunosuppressive drugs within 2 weeks prior to the first dose of the study drug, with the exception of using corticosteroids for local inflammation or prevention of allergies, nausea, and vomiting. Other special circumstances should be communicated with the investigator. In the absence of active autoimmune diseases, inhaled or locally applied steroids and adrenal cortex hormones that replace a dosage of \>10 mg/day prednisone can be used.
e) Vaccination with anti-tumor vaccines or receipt of live vaccines within 4 weeks prior to the first dose of the study drug; f) underwent major surgery or had any serious trauma within 4 weeks prior to the first dose of the study drug.
5. Toxicity from previous anti-cancer therapy has not recovered to ≤ CTCAE grade 1 (excluding alopecia and residual neurotoxicity related to previous platinum therapy) or does not meet inclusion/exclusion criteria.
6. Serious infection (CTCAE grade \>2) within 4 weeks prior to the first dose of the study drug, including severe pneumonia, sepsis requiring hospitalization, and infection-related complications; baseline chest imaging shows active pulmonary inflammation, symptoms and signs of infection within 4 weeks of first dose, or the need for oral or intravenous antibiotics.
7. Active autoimmune diseases or a history of autoimmune diseases (including but not limited to interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism), except autoimmune-mediated hypothyroidism treated with a stable dose of thyroid replacement hormone and I-type diabetes treated with a stable dose of insulin. Patients with vitiligo or childhood asthma/allergy in remission without any intervention in adulthood are not excluded.
8. A history of immunodeficiency diseases, including HIV-positive, other acquired or congenital immunodeficiency diseases, organ transplantation, or allogeneic bone marrow transplantation.
9. A history of interstitial lung disease (excluding radiation pneumonitis that has not been treated with steroids), and a history of non-infectious pneumonia.
10. Evidence of active tuberculosis infection based on medical history and CT examination, a history of active tuberculosis infection within 1 year prior to screening, or a history of active tuberculosis infection over 1 year ago that has not been properly treated.
11. Patients with active hepatitis B (HBV DNA ≥500 IU/mL or 2500 copies/mL) or hepatitis C (positive HCV antibodies and HCV-RNA higher than the detection limit of the assay) are excluded. Patients with HBsAg-positive and HBV DNA-negative or HBV DNA \<500 IU/mL or 2500 copies/mL can receive treatment for antiviral therapy for more than 2 weeks before enrolling in the trial and continue antiviral therapy for 6 months after the end of the last dose of the study drug.
12. A known history of psychotropic substance abuse, alcoholism or drug use;
13. Pregnant or lactating women;
14. At the investigator's discretion, patients with other factors that may force them to withdraw from the study, such as concomitant severe illnesses (including mental illness) requiring treatment, significant laboratory abnormalities, and family or social factors that may hinder patient safety or data collection.
15. Patients with severe active bleeding, active peptic ulcers, unhealed gastrointestinal perforations, or gastrointestinal fistulas.
