This is a two-part, biomarker-guided Phase 1/2 study evaluating the safety, feasibility, and preliminary anti-tumor activity of off-the-shelf dual-target CAR-NK cells in participants with advanced or metastatic NSCLC whose tumors co-express at least two of the following antigens: Mesothelin (MSLN), EGFR, and HER2/ERBB2.

Participants will receive lymphodepleting chemotherapy followed by infusion of the CAR-NK product matched to their tumor antigen profile. A data-driven interim assessment will be used to select the most suitable construct for expansion.

The study includes Part A (dose escalation) and Part B (dose expansion). In Part A, participants are assigned to one of three dual-target CAR-NK constructs based on tumor antigen co-expression (IHC and/or RNA profiling): MSLN/EGFR, MSLN/HER2, or EGFR/HER2. Dose escalation within each construct follows a standard 3+3 design to identify a recommended Phase 2 dose (RP2D).

In Part B, the study expands at the RP2D and may adaptively prioritize the construct demonstrating the most favorable benefit-risk profile .

Key exploratory objectives include CAR-NK persistence, immune pharmacodynamics, cytokine profiling, and correlations between antigen density and clinical outcomes.

Inclusion Criteria:

• Histologically or cytologically confirmed NSCLC that is unresectable Stage IIIB/IIIC or Stage IV, with radiographic progression on or after standard-of-care therapy (including platinum-based chemotherapy and immune checkpoint inhibitor when appropriate).
• At least one measurable lesion per RECIST v1.1.
• Archival tumor tissue available (or willingness to undergo a fresh biopsy) for antigen testing.
• Tumor co-expression of at least two of the following antigens at screening: MSLN, EGFR, HER2/ERBB2.

Example thresholds: IHC ≥2+ in ≥50% of tumor cells for each required antigen (or an equivalent RNA expression threshold).

• ECOG performance status 0-1.
• Adequate organ function (hematologic, hepatic, renal) as defined by protocol laboratory limits.
• Life expectancy ≥12 weeks.
• Negative pregnancy test for individuals of childbearing potential; agreement to use effective contraception for the study-defined period.
• Ability to understand and willingness to sign written informed consent.

Exclusion Criteria:

• Active, uncontrolled central nervous system (CNS) metastases. Participants with previously treated/stable CNS disease may be eligible if clinically stable and off high-dose corticosteroids.
• Prior gene-modified cellular therapy (e.g., CAR-T, CAR-NK, TCR-T) within 3 months, or any prior therapy that in the investigator's judgment increases risk of severe toxicity.
• History of severe cytokine release syndrome (CRS) or immune effector cell-associated neurotoxicity syndrome (ICANS) with prior therapies.
• Clinically significant interstitial lung disease or pneumonitis requiring systemic steroids, or uncontrolled pulmonary comorbidity that would confound toxicity monitoring.
• Active autoimmune disease requiring systemic immunosuppression (physiologic steroid replacement permitted).
• Active uncontrolled infection, including uncontrolled HIV, active hepatitis B, or active hepatitis C infection.
• Significant cardiovascular disease (e.g., recent myocardial infarction, unstable angina, uncontrolled arrhythmia, or LVEF below institutional lower limit).
• Pregnant or breastfeeding.
• Concurrent anti-cancer therapy (chemotherapy, targeted therapy, immunotherapy) within protocol-defined washout periods.
• Any condition that, in the investigator's opinion, would interfere with participant safety or compliance

Open-label due to early-phase safety monitoring and individualized product assignment