This is a multi-center, open-label investigator-initiated trial (IIT) designed to evaluate the safety, tolerability, and feasibility of combined intracranial and intravenous administration of ex vivo expanded and activated natural killer (NK) cells in adult patients with malignant solid brain tumors who have failed standard treatment modalities. The primary objective is to determine the maximum tolerated dose (MTD) or maximum feasible dose (MFD) of the combined NK cell therapy. Secondary objectives include preliminary assessment of anti-tumor activity as measured by progression-free survival (PFS), overall survival (OS), objective response rate (ORR) per RANO criteria, and evaluation of the immunological effects of NK cell infusion in the tumor microenvironment and peripheral blood.

Inclusion Criteria:

1. Male or female, age 18-70 years old (both ends included)

2. At least one evaluable lesion with previous biopsy or pathohistologic confirmation of malignant central nervous system tumor, with imaging suggestive of continued progression or recurrence after comprehensive treatment

3. Karnofsky Performance Status (KPS) ≥ 60%

4. Life expectancy > 4 weeks, and must be able to undergo an MRI with contrast

5. Patients who completed radiotherapy or systemic therapies (including temozolomide/bevacizumab or other agents) for at least 4 weeks prior to enrollment. All prior treatment-related toxicities should be defined as ≤ grade 1 (except for toxicities such as alopecia or leukoplakia) according to the Common Terminology Standard for Adverse Events (CTCAE 6.0)

6. Dexamethasone dose ≤ 4 mg/day or equivalent corticosteroid dose, or no dexamethasone administered

7. Must have adequate organ and marrow function as defined below:

   • White blood cell count (WBC) ≥ 3 x 10^9/L
   • Absolute neutrophil count (ANC) > 1 x 10^9/L
   • Hemoglobin (Hb) ≥ 90 g/L
   • Platelet (PLT) ≥ 80×10^9/L
   • Albumin transaminase (ALT) & albumin transaminase (AST) < 1.5 × institutional upper limit of normal (ULN)
   • Serum creatinine (Cr) < 1.5 x institutional ULN
   • Total bilirubin < 1.5 x institutional ULN
   • PT & PTT ≤ 1.25 x institutional ULN

8. No obvious hereditary diseases

9. Normal cardiac function with left ventricular ejection fraction >55%

10. No bleeding and coagulation disorders

11. Absence of positive blood cultures for bacteria, fungus, or virus within 48-hours prior to NK cell infusion and/or there aren't any indications of meningitis

12. Fertile women must have had a pregnancy test with a negative result within 7 days prior to the start of treatment, and subjects are willing to use contraception (hormonal or barrier method of birth control or abstinence) during the clinical trial and for 6 months after the last cell infusion; should a woman become pregnant or suspect that she is pregnant while participating on the trial, she should inform her treating physician immediately

13. Signed, written informed consent

Exclusion Criteria:

1. Active hepatitis B or C virus, HIV infection, or other untreated active infection
2. Pregnant and lactating women
3. Participants with organ failure
4. Participants with a chronic disease requiring immunologic or hormonal therapy
5. Participants with an allergy to immunotherapy and related cells
6. Participants with uncontrolled intercurrent illness
7. Participants with psychiatric illness/social situations that would limit compliance with study requirements
8. Participants with a history of organ transplantation or who are awaiting organ transplantation