Cellular immunotherapy for lung cancer: current clinical evidence, translational challenges, and future perspectives: a narrative review.

BACKGROUND AND

OBJECTIVE

Lung cancer remains a leading cause of cancer-related mortality. Cellular immunotherapy has achieved major advances in hematologic malignancies, but translation to lung cancer is constrained by antigen heterogeneity, limited trafficking and persistence, an immunosuppressive tumor microenvironment (TME), manufacturing complexity, and on-target off-tumor toxicity. This narrative review summarizes current clinical evidence, major translational barriers, and future development strategies for cellular immunotherapy in lung cancer.

METHODS

PubMed, Web of Science, Embase, and ClinicalTrials.gov were searched from database inception to 1 June 2026 using Medical Subject Headings (MeSH) and free-text terms. Evidence on chimeric antigen receptor T-cell (CAR-T), T-cell receptor-engineered T-cell (TCR-T), tumor-infiltrating lymphocyte (TIL), natural killer (NK), chimeric antigen receptor natural killer (CAR-NK), and cancer vaccine-based strategies was reviewed, with priority given to non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC).

KEY CONTENT AND FINDINGS: Most lung-cancer cellular therapy studies remain early phase. TIL therapy has demonstrated clinical activity in NSCLC, while EGFR, MSLN, CEA, MUC1, PD-L1, B7-H3, and DLL3 are representative targets under investigation for CAR-based approaches; NY-ESO-1 and KK-LC-1 are representative TCR-T targets. Major barriers include antigen escape, poor tumor infiltration, HLA restriction or loss, immunosuppressive signaling, cellular exhaustion, limited persistence, manufacturing burden, and treatment-related toxicity. Current optimization strategies include gene editing, chemokine-receptor engineering, armored or logic-gated receptors, safety switches, optimized lymphodepletion, and rational combinations with other anticancer therapies.

CONCLUSIONS

Cellular immunotherapy is a promising but still developing strategy for lung cancer. Future studies should prioritize biomarker-guided patient selection, safer and more persistent cell products, scalable manufacturing, and prospective clinical validation of rational combination strategies.