CD47: The Next Frontier in Immune Checkpoint Blockade for Non-Small Cell Lung Cancer

Simple Summary Lung cancer is the leading cause of cancer-related death worldwide. Despite treatment advances, high rates of tumor recurrence emphasize the need for new therapeutic strategies. Tumors often acquire mechanisms to avoid detection by the immune system, allowing them to develop and metastasize. Immunotherapy is a type of treatment designed to overcome these mechanisms by reactivating the immune system to eliminate tumors. CD47 is a cell surface protein and marker of "self" expressed on cells throughout the body and prevents them from being "eaten" by cells of the immune system. Lung cancers exploit this "don't eat me" signal by upregulating CD47 to evade the immune system, making it a promising therapeutic target. This review summarizes the roles of CD47 in tumor biology, its therapeutic potential in non-small cell lung cancer, and challenges that must be overcome to facilitate the clinical translation of CD47-targeted immunotherapy to improve lung cancer survival rates.Abstract The success of PD-1/PD-L1-targeted therapy in lung cancer has resulted in great enthusiasm for additional immunotherapies in development to elicit similar survival benefits, particularly in patients who do not respond to or are ineligible for PD-1 blockade. CD47 is an immunosuppressive molecule that binds SIRP alpha on antigen-presenting cells to regulate an innate immune checkpoint that blocks phagocytosis and subsequent activation of adaptive tumor immunity. In lung cancer, CD47 expression is associated with poor survival and tumors with EGFR mutations, which do not typically respond to PD-1 blockade. Given its prognostic relevance, its role in facilitating immune escape, and the number of agents currently in clinical development, CD47 blockade represents a promising next-generation immunotherapy for lung cancer. In this review, we briefly summarize how tumors disrupt the cancer immunity cycle to facilitate immune evasion and their exploitation of immune checkpoints like the CD47-SIRP alpha axis. We also discuss approved immune checkpoint inhibitors and strategies for targeting CD47 that are currently being investigated. Finally, we review the literature supporting CD47 as a promising immunotherapeutic target in lung cancer and offer our perspective on key obstacles that must be overcome to establish CD47 blockade as the next standard of care for lung cancer therapy.