Abstract
Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide. Immunotherapy targeting the PD-1/PD-L1 axis has revolutionized treatment, providing durable responses in a subset of patients. However, with fewer than 50% of patients achieving significant benefits, there is a critical need to expand therapeutic strategies. This review explores emerging targets in immune checkpoint inhibition beyond PD-1/PD-L1, including CTLA-4, TIGIT, LAG-3, TIM-3, NKG2A, and CD39/CD73. We highlight the biological basis of CD8 T cell exhaustion in shaping the antitumor immune response. Novel therapeutic approaches targeting additional inhibitory receptors (IR) are discussed, with a focus on their distinct mechanisms of action and combinatory potential with existing therapies. Despite significant advancements, challenges remain in overcoming resistance mechanisms and optimizing patient selection. This review underscores the importance of dual checkpoint blockade and innovative bispecific antibody engineering to maximize therapeutic outcomes for NSCLC patients.