Lung cancer (LC) is the leading cause of
cancer-related deaths worldwide. Traditional therapeutic approaches such as
chemotherapy or
radiotherapy have provided only a marginal improvement in the treatment of lung
carcinomas. Inhibitors targeting specific genetic aberrations present in
non-small cell lung cancer (NSCLC), the most common subtype (85%), have improved the prognostic outlook, but due to the complexity of the LC mutational spectrum, only a fraction of patients benefit from these
targeted molecular therapies. More recently, the realization that the immune infiltrate surrounding solid
tumors can foster
tumor-promoting
inflammation has led to the development and implementation of anticancer
immunotherapies in the clinic. In NSCLC, one of the most abundant leukocyte infiltrates is macrophages. These highly
plastic phagocytes, which are part of the cellular repertoire of the innate immunity, can have a pivotal role in early NSCLC establishment, malignant progression, and
tumor invasion. Emerging macrophage-targeting
therapies have been focused on the re-differentiation of the macrophages toward an antitumorigenic phenotype, depletion of
tumor-promoting macrophage subtypes, or combination
therapies combining traditional cytotoxic treatments with immunotherapeutic agents. The most extensively used models employed for the exploration of NSCLC biology and
therapy have been 2D cell lines and murine models. However, studying
cancer immunology requires appropriately complex models. 3D platforms, including organoid models, are quickly advancing powerful tools to study immune cell-epithelial cell interactions within the tumor microenvironment. Co-cultures of immune cells along with NSCLC organoids allow for an in vitro observation of the tumor microenvironment dynamics closely resembling in vivo settings. Ultimately, the implementation of 3D organoid technology into tumor microenvironment-modeling platforms might facilitate the exploration of macrophage-targeted
therapies in NSCLC immunotherapeutic research, thus establishing a new frontier in NSCLC treatment.