Abstract
Lung cancer remains the leading cause of cancer-related mortality worldwide, and current therapies offer limited survival benefit for patients with advanced disease. While immune checkpoint inhibitors and targeted therapies have improved outcomes in some populations, most patients either fail to respond or develop acquired resistance, highlighting the need for more potent and durable immunotherapeutic strategies. Next-generation immune cell therapies, including chimeric antigen receptor T cells (CAR T), chimeric antigen receptor natural killer cells (CAR NK), and tumor-infiltrating lymphocytes (TIL), provide a promising approach for lung cancers that are refractory to conventional treatment. These therapies leverage the patient's own immune system or engineered immune cells to directly recognize and eliminate malignant cells, while potentially overcoming immunosuppressive tumor microenvironments. This review provides a comprehensive synthesis of recent advances in the design, engineering, and clinical development of CAR T, CAR NK, and TIL therapies in both non-small cell and small cell lung cancer. We discuss preclinical and early clinical studies demonstrating feasibility, safety, and mechanisms of action, including antigen targeting, immune cell persistence, trafficking, and intratumoral activity. Key challenges, such as tumor antigen heterogeneity, immune suppression, limited durability, and off-tumor toxicity, are critically evaluated. We also examine emerging strategies to enhance efficacy, including multi-antigen targeting, armored and logic-gated constructs, regional delivery, combination with checkpoint inhibition or other modulators, and scalable off-the-shelf manufacturing platforms. Collectively, these next-generation immune cell therapies represent a rapidly evolving and translationally relevant approach that may expand therapeutic options, improve survival, and provide durable antitumor responses in patients with lung cancer who have exhausted conventional therapies.