Immune checkpoints in lung cancer

The advent of immune checkpoint inhibitors (ICIs) has revolutionised the management of lung cancer, transforming it from a historically immune-resistant malignancy into a paradigm for durable immunotherapy response. This review provides a comprehensive overview of the biological and clinical foundations of checkpoint regulation in the lung and their implications for patient care. We first explore the unique pulmonary immune environment, where continuous exposure to environmental antigens necessitates a delicate balance between tolerance and defence. Within this context, immune checkpoints, such as programmed cell death protein 1 (PD-1) and its ligand PD-L1 as well as cytotoxic T-lymphocyte-associated protein 4, maintain physiological self-tolerance but can be subverted by tumour cells to evade immune surveillance. Emerging inhibitory receptors, including LAG-3, TIGIT and TIM-3, contribute additional layers of immune regulation and resistance, highlighting opportunities for combinatorial therapeutic strategies. The clinical section summarises pivotal trials establishing ICIs as the standard of care across metastatic, locally advanced and early-stage lung cancer. These agents now span the full disease continuum, from neoadjuvant and adjuvant to perioperative and consolidation settings. We also address the management of immune-related adverse events and the need for precision in patient selection through biomarkers, such as PD-L1 expression, tumour mutational burden and circulating immune signatures. Finally, we discuss ongoing challenges, including mechanisms of primary and acquired resistance, and emerging approaches integrating spatial multi-omics, dynamic immune monitoring and microbiome profiling. Together, these advances are reshaping lung cancer immunotherapy towards a more precise, adaptive and durable model of care.