Adoptive cell therapy in lung cancer: progress, challenges, and prospects

Lung cancer is the leading cause of cancer-related deaths worldwide. Over the past decade, immunotherapy, represented by immune checkpoint inhibitors (ICIs) targeting programmed cell death protein-1/programmed cell death protein ligand-1 (PD-1/PD-L1) or cytotoxic T lymphocyte associated antigen-4 (CTLA-4), has revolutionized the treatment paradigm of lung cancer, reducing the risk of death by approximately 30%. However, approximately 70% of patients with advanced non-small cell lung cancer are either non-responsive to ICIs or initially respond to treatment but eventually experience disease progression due to acquired resistance. This subset of non-responsive or ultimately resistant patients is often characterized by complete exhaustion of endogenous anti-tumor T cells, which are unable to exert anti-tumor effects, thereby leading to ICI non-response or resistance. Correspondingly, the adoptive transfer of immune cells has shown promising efficacy in numerous clinical studies involving this patient population. Nevertheless, the Food and Drug Administration (FDA) has not yet approved any cell therapy strategy for lung cancer, primarily because of factors such as the hostile tumor microenvironment and T cell exhaustion. Herein, we summarize the current progress in cell therapy for lung cancer, analyze key challenges, and propose potential solutions.