This is a single-arm study designed to evaluate the safety and efficacy of TILs combined with third-generation EGFR-TKIs therapy for patients with EGFR-mutant NSCLC resistant to TKI.

This study is an open-label, single-arm, prospective clinical trial. 50 subjects with advanced EGFR-TKI-resistant NSCLC, including those complicated with malignant pleural effusion, will be enrolled and receive TILs infusion combined with third-generation EGFR-TKIs. Adverse reactions, therapeutic efficacy and other relevant indicators will be closely observed and followed up to systematically evaluate the safety and efficacy of this combined regimen.

Inclusion Criteria:

• (1) Age 18-75 years, male or female; (2) Patients with a history of surgical resection, pathologically diagnosed with NSCLC, genetically tested for EGFR mutation, who experienced disease progression (local recurrence or distant metastasis) after EGFR-TKI treatment and refused chemotherapy or other therapies; (3) Ability to obtain approximately 5 tumor samples via surgery, biopsy, or bronchoscopy for preparation of autologous tumor-infiltrating lymphocytes; (4) ECOG performance status score of 0-2; (5) HGB ≥70 g/L, transfusion-eligible; (6) No severe hepatic, renal, cardiac, or pulmonary dysfunction, with the following requirements met: Creatinine ≤ 1.5 × ULN; Oxygen saturation > 90%; Total bilirubin ≤ 1.5 × ULN; ALT and AST ≤ 2.5 × ULN; (7) Expected survival > 3 months; complete clinical documentation.

Exclusion Criteria:

• (1) Patients with pathological diagnosis of small cell lung cancer components; (2) Patients who have previously undergone organ transplantation or cytoreductive therapy including lymph node clearance; (3) Patients currently receiving immunotherapy or steroid therapy; (4) Patients with concurrent severe or persistent infections that cannot be effectively controlled; (5) Patients with concurrent severe autoimmune diseases or congenital immunodeficiency; (6) History of severe allergic reactions to biological products (including antibiotics); (7) Active hepatitis (quantitative hepatitis B virus DNA [HBV-DNA] above the lower limit of detection for the assay method, or positive hepatitis C antibodies [HCV-Ab] with HCV-RNA above the lower limit of detection for the assay method); (8) HIV infection or syphilis infection; (9) Female patients who are pregnant, breastfeeding, or planning pregnancy within 12 months; (10) Conditions deemed by the investigator to potentially increase subject risk or interfere with trial results.