Immune checkpoints in lung cancer.

Area of Science:

• Oncology
• Immunology
• Pulmonary Medicine

Background:

• Lung cancer was historically immune-resistant, but immunotherapy has revolutionized its management.
• The pulmonary immune environment requires a balance between defense and tolerance, which tumors can exploit.
• Immune checkpoints like PD-1/PD-L1 and CTLA-4 are crucial for self-tolerance but can be subverted by cancer cells.

Purpose of the Study:

• To provide a comprehensive review of immune checkpoint regulation in lung cancer.
• To discuss the biological and clinical foundations of immune checkpoint inhibitors (ICIs) in lung cancer.
• To explore emerging strategies for overcoming resistance and improving immunotherapy outcomes.

Main Methods:

• Review of biological mechanisms of immune checkpoints (PD-1, PD-L1, CTLA-4, LAG-3, TIGIT, TIM-3).
• Summary of pivotal clinical trials establishing ICIs as standard of care in various lung cancer stages.
• Discussion of biomarkers, immune-related adverse events, and resistance mechanisms.

Main Results:

• ICIs are now standard care across metastatic, locally advanced, and early-stage lung cancer.
• Emerging checkpoints offer opportunities for combinatorial therapies.
• Biomarkers like PD-L1 expression and tumor mutational burden aid patient selection.

Conclusions:

• ICIs have reshaped lung cancer management, offering durable responses.
• Addressing resistance and optimizing patient selection are key challenges.
• Future directions include spatial multi-omics, immune monitoring, and microbiome profiling for precise, adaptive immunotherapy.