CAR-NK Cell Biology and Engineering for Solid Tumors, With a Focus on Lung Cancer

Over the past decade, chimeric antigen receptor (CAR) T-cell therapy has revolutionized cancer immunotherapy, demonstrating remarkable efficacy in treating relapsed or refractory hematologic malignancies across both pediatric and adult populations. In parallel, CAR-engineered natural killer (CAR-NK) cells have emerged as a complementary and promising alternative to CAR-T therapy, offering several inherent advantages. Unlike CAR-T cells, CAR-NK cells operate independently of major histocompatibility complex (MHC) compatibility and are associated with a lower risk of adverse immune reactions. They also provide practical benefits, such as the potential for standardized, "off-the-shelf" therapeutic formulations. Consistent and encouraging outcomes have been reported with CAR-NK cell therapy in hematologic cancers; however, their success against solid tumors remains constrained by multiple challenges, including limited tumor infiltration, suboptimal trafficking, and the immunosuppressive characteristics of the tumor microenvironment. Importantly, lung cancer presents indication-specific barriers to cellular immunotherapy, including profound inter and intratumoral heterogeneity, a highly immunosuppressive pulmonary tumor microenvironment, and a narrow safety margin in a vital organ where inflammation or edema can rapidly impair gas exchange. These factors limit the depth and durability of responses achieved with current systemic modalities in a substantial fraction of patients and also constrain adoptive cell therapy in thoracic malignancies. Therefore, lung cancer represents both a compelling and stringent setting to develop safer and more durable engineered cellular platforms such as CAR-NK cells. Lung cancer, one of the most prevalent and lethal malignancies worldwide, still depends largely on conventional treatment modalities such as surgery, chemotherapy, radiotherapy, and targeted agents. Accordingly, we organize this review around lung cancer-specific design constraints, antigen heterogeneity/escape, impaired trafficking into pulmonary tumors, an immunosuppressive lung microenvironment, and a narrow pulmonary safety window, and map each constraint to actionable CAR-NK engineering and combination strategies.