The Adenosinergic Pathway in Non-Small Cell Lung Cancer

Simple Summary Lung cancer remains the most important cause of cancer-related mortality worldwide. Immune checkpoint inhibitors revolutionized lung cancer care. These molecules restore the host's immune response against tumor cells and led to impressive results in non-small cell lung cancer patients. However, these benefits are only observed in a minority of patients. Extracellular adenosine is an immune checkpoint that contributes to immune evasion in tumor cells. Current research focuses on targeting this pathway with the aim of inducing durable treatment effects in a greater proportion of lung cancer patients.Abstract Immune checkpoint inhibitors (ICIs) targeting PD-(L)1 and CTLA-4 have revolutionized the systemic treatment of non-small cell lung cancer (NSCLC), achieving impressive results. However, long-term clinical benefits are only seen in a minority of patients. Extensive research is being conducted on novel potential immune checkpoints and the mechanisms underlying ICI resistance. The tumor microenvironment (TME) plays a critical role in modulating the immune response and influencing the efficacy of ICIs. The adenosinergic pathway and extracellular adenosine (eADO) are potential targets to improve the response to ICIs in NSCLC patients. First, this review delves into the adenosinergic pathway and the impact of adenosine within the TME. Second, we provide an overview of relevant preclinical and clinical data on molecules targeting this pathway, particularly focusing on NSCLC.