This study assesses the safety and efficacy of NK510 combined with PD-(L)1 inhibitors for relapsed/refractory advanced NSCLC, with two administration routes: intravenous infusion and intrapleural perfusion for malignant pleural effusion. Eligible patients need confirmed measurable lesions; intravenous cohort requires EGFR/ROS1/ALK negativity and disease progression after PD-(L)1 inhibitor treatment, while intrapleural cohort accepts targeted therapy-resistant patients with ≥500ml pleural effusion, and the treatment's safety, efficacy and immune microenvironment changes will be evaluated.

Inclusion Criteria:

• Age ≥ 18 years, male or female.
• For dose expansion group (Group A/B/C):

A. EGFR mutation-negative, ROS1-negative, and ALK-negative; unresectable and non-radiotherapeutic stage III or IV, locally advanced, recurrent or metastatic NSCLC.

B. Disease progression after ≥4 courses of PD-(L)1 blockade ± chemotherapy.

• For pleural perfusion group (Group D1/D2): Advanced NSCLC with malignant pleural effusion ≥500ml (confirmed by B-ultrasound or CT); patients with driver gene-positive and resistant to targeted therapy are acceptable.
• At least one CT or MRI measurable lesion according to RECIST v1.1.
• ECOG performance status 0-2.
• Expected survival ≥3 months.
• All toxicities from previous anti-tumor therapy (except alopecia and fatigue) resolved to grade 1 (CTCAE v5.0) or baseline; subjects with long-term sequelae from previous therapy (e.g., neuropathy after platinum-based therapy) are acceptable.
• Fertile females must be non-lactating and have a negative serum pregnancy test within 1 week before enrollment; all subjects (male or female) must agree to use contraception from signing informed consent until 6 months after the last NK510 infusion.
• Able to comply with the study protocol and follow-up procedures.
• Voluntarily sign the informed consent form.

Exclusion Criteria:

• Symptomatic central nervous system (CNS) metastasis and/or carcinomatous meningitis.

• Active, known or suspected autoimmune diseases (excluding type 1 diabetes, hypothyroidism requiring only hormone replacement therapy, skin diseases not requiring systemic treatment [e.g., vitiligo, psoriasis, alopecia] or diseases not expected to recur without external triggers).

• History of severe cardiovascular and cerebrovascular diseases, including but not limited to: severe cardiac arrhythmia or conduction abnormalities requiring clinical intervention (e.g., ventricular arrhythmia, grade III atrioventricular block); QTc interval >480 ms on 12-lead ECG at rest; acute coronary syndrome, congestive heart failure, aortic dissection, stroke or other grade ≥3 cardiovascular and cerebrovascular events within 6 months before enrollment; NYHA cardiac function class ≥II or left ventricular ejection fraction (LVEF) <50%; clinically uncontrolled hypertension.

• Blood transfusion, erythropoietin, granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor treatment within 2 weeks before enrollment.

• Systemic treatment with corticosteroids (prednisone >10 mg/day or equivalent) or other immunosuppressive/immunomodulatory drugs (e.g., thymosin, interleukin-2, interferon) within 2 weeks before enrollment; inhalation or topical corticosteroids are allowed in subjects without active autoimmune diseases.

• Known allergy or intolerance to PD-(L)1 blockade.

• Meeting any of the following laboratory criteria:

  1. Hematology: Neutrophils <1.5×10⁹/L; Platelets <75×10⁹/L; Hemoglobin <90 g/L.
  2. Liver function: ALT >3×ULN (≥5×ULN in patients with liver metastasis); AST >3×ULN (≥5×ULN in patients with liver metastasis); TBIL >1.5×ULN or >2.5×ULN (3.0 mg/dL) in patients with Gilbert syndrome.
  3. Renal function: Serum creatinine >1.5×ULN or creatinine clearance <50 mL/min.

• Any other severe or uncontrollable medical diseases, active infections, physical examination abnormalities, laboratory test abnormalities, mental status changes or mental illnesses that increase subject risk or affect study results (assessed by investigator).