Inclusion Criteria:
1. Aged 18-75 years old, male or female;
2. Patients with pathologically diagnosed non-small cell lung cancer with cerebrospinal fluid and/or MRI diagnosis of leptomeningeal metastasis;
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 4;
4. Expected survival time of at least 4 weeks;
5. Oncologist clarification of the potential necessity of receiving systemic therapy for metastatic tumors outside the CNS;
6. Previous radiation therapy, including whole brain radiation, stereotactic radiosurgery, or stereotactic body radiation therapy (SBRT), which must be completed at least 7 days prior to the start of treatment;
7. Patients who have received approved targeted therapies (EGFR inhibitors, ALK inhibitors, or other targeted therapeutic agents), and other systemic therapies will be allowed to remain on concurrent therapy; concurrent intrathecal therapy with other agents will not be allowed.
8. Laboratory test indicators meet the following criteria:
1. Bone marrow function: hemoglobin (Hb) ≥80g/L; white blood cell count (WBC) ≥lower limit of normal; absolute neutrophil count (ANC) ≥1.5×10\^9 /L; platelet count ≥70×109 /L;
2. Renal function: Cr ≤ ULN (upper limit of normal) × 1.5, endogenous creatinine clearance (Ccr) ≥ 55 ml/min;
3. Liver function: total bilirubin ≤ ULN × 1.5; ALT and AST ≤ ULN × 2.5; (if there is liver metastasis, total bilirubin is not higher than 3 times the upper limit of normal, and transaminases are not higher than 5 times the upper limit of normal);
4. Coagulation function: international normalized ratio of prothrombin time ≤ ULN × 1.5, and partial thromboplastin time within the normal value;
9. Females of child-bearing potential agree to use contraception during the study period and for 6 months after the completion of the study; patients who have had a negative serum or urine pregnancy test within seven days prior to enrollment in the study and who are not breastfeeding; and males agreeing to use contraception during the study period and for 6 months after the completion of the study;
10. Those who have not participated in another drug clinical trial within 4 weeks prior to enrollment;
11. Subjects who can understand the study situation and voluntarily sign the informed consent form;
12. Patients are expected to be compliant and able to follow up on efficacy and adverse events according to protocol requirements.
Exclusion Criteria:
1. Diagnosis of other malignant tumors (except carcinoma in situ, basal cell carcinoma, etc.) within the previous 5 years;
2. History of allergy to pemetrexed and ICIs therapy;
3. Any previous intrathecal injection therapy;
4. Rule out differential diagnosis of LM:a. Aseptic meningitis b. Viral meningitis c. Bacterial meningitis;
5. Participation in other clinical trials or observation periods;
6. Clinical conditions that would interfere with the evaluation or interpretation of safety or findings, or impede the understanding of informed consent and compliance with protocol requirements;
7. Presence of any treatment-related toxicity from prior systemic antitumor therapy other than alopecia that does not meet CTCAE grade 1 (based on CTCAE 5.0);
8. Presence of any active autoimmune disease or history of autoimmune disease; immunodeficiency, active tuberculosis, hepatitis B ( hepatitis B virus titer HBV-DNA \<500 IU/ml after treatment and if liver function is normal will be allowed), or positive test for hepatitis C virus.
9. Either disease resulting in permanent immunosuppression or requiring permanent immunosuppressive therapy;
10. Presence of active infection or serious comorbidities;
11. uncontrolled epilepsy, neurologic failure, or severe neurologic impairment related to treatment;
12. Presence of hereditary or acquired bleeding and thrombotic tendencies;
13. History of severe injury or surgery within 1 month prior to enrollment;
14. Treatment with a live or attenuated vaccine used for the prevention of infectious diseases within 30 days prior to the first administration (injectable seasonal influenza vaccine is permitted);
15. Inability to complete an enhanced MRI;
16. Treatment with immunosuppressive drugs or corticosteroids (\> 10 mg prednisone or equivalent per day) within 14 days prior to enrollment; patients are allowed to receive steroid therapy to control CNS-related symptoms, but the dose must ≤ 5 mg per day of dexamethasone (or equivalent); in the absence of an active autoimmune disease, inhaled or topical steroids and adrenal gland replacement dosing are acceptable; alternative therapies (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) are permitted; patients with experimental medications that require premedication with corticosteroids are not restricted;
17. Individuals considered by the investigator to be unsuitable for enrollment.
