Unraveling the Intricacies of CD73/Adenosine Signaling: The Pulmonary Immune and Stromal Microenvironment in Lung Cancer

Simple Summary CD73 and adenosine are garnering significant attention in lung cancer research. CD73, an enzyme crucial for adenosine production, is found in various cells, including immune cells, within our lungs. During stress or cancer, adenosine levels increase from their usual low levels. Notably, lung tumor cells, particularly non-small cell lung cancer, express substantial CD73. The CD73 expression in the resident lung cells and immune cells may set an environment prone to cancer development, underscoring the importance of understanding cell interactions governing tumoral growth and behavior. Presently, the treatment with immune checkpoint inhibitors aims to help our body fight cancer; however, they do not work for every patient. Researchers propose targeting CD73 and adenosine to enhance these treatments to work better. CD73 acts as a "stop" signal for immune cells fighting cancer, a role immune checkpoint inhibitors aim to reverse. Blocking CD73 might amplify treatment effectiveness. Beyond this, CD73 shapes immune cell interactions and activity against cancer. Deciphering CD73 and adenosine's roles in lung cancer may potentially reshape the therapeutic landscape and offer novel therapeutic opportunities.Abstract CD73 and adenosine have gained prominence in lung cancer research. The NT5E gene encodes CD73, known as an ectonucleotidase, which plays a crucial role within tumor cells, with immune-suppressive properties. Beyond cancer, CD73 exerts an influence on cardiac, neural, and renal functions, affecting cardiac, neural, and renal functions. CD73's significance lies in its production of extracellular adenosine. It is notably expressed across diverse cell types within the immune and stromal lung microenvironment. CD73 expression amplifies in lung tumors, especially non-small cell lung cancer (NSCLC), often aligned with key oncogenic drivers like mutant EGFR and KRAS. CD73/adenosine pathway seems to be involved in tumoral immunoevasion, hampering the use of the immune checkpoint inhibitor (ICI) and correlating with therapy resistance. Despite the partial success of current ICI therapies, the CD73/adenosine pathway offers promise in enhancing their effectiveness. This comprehensive review explores recent insights into lung cancer's CD73/adenosine pathway. It explores roles within tumor cells, the lung's stromal environment, and the immune system. Ranging from pre-clinical models to clinical trials, potential therapies targeting the adenosine pathway for lung cancer treatment are discussed below.