Simple SummaryThe development of targeted therapies has led to personalized medicine for advanced non-small cell lung cancer (NSCLC), particularly in lung adenocarcinoma (ADC) with actionable genetic alterations, such asEGFR,ALK,KRAS, andROS1. Tyrosine kinase inhibitors (TKIs) and angiogenesis inhibitors have shown better therapeutic responses and lower toxicity compared to systemic chemotherapy. However, resistance to these therapies remains a challenge. Immune checkpoint inhibitors (ICIs) targeting PD-1 or PD-L1 have changed the treatment paradigm for NSCLC without actionable genetic alterations, but combining targeted therapy and ICIs does not provide survival benefits. The review focuses on the tumor immune microenvironment and its role in applying ICIs for this subpopulation of lung ADC patients.AbstractThe rapid development of targeted therapy paved the way toward personalized medicine for advanced non-small cell lung cancer (NSCLC). Lung adenocarcinoma (ADC) harboring actionable genetic alternations including epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), Kirsten rat sarcoma virus (ALK) and c-ros oncogene 1 (ROS1) treated with tyrosine kinase inhibitors (TKIs) incurred lesser treatment toxicity but better therapeutic responses compared with systemic chemotherapy. Angiogenesis inhibitors targeting vascular endothelial growth factor (VEGF) have also shown an increase in overall survival (OS) for NSCLC patients. However, acquired resistance to these targeted therapies remains a major obstacle to long-term maintenance treatment for lung ADC patients. The emergence of immune checkpoint inhibitors (ICIs) against programmed cell death protein 1 (PD-1) or programmed cell death-ligand 1 (PD-L1) has changed the treatment paradigm for NSCLC tumors without actionable genetic alternations. Clinical studies have suggested, however, that there are no survival benefits with the combination of targeted therapy and ICIs. In this review, we will summarize and discuss the current knowledge on the tumor immune microenvironment and the dynamics of immune phenotypes, which could be crucial in extending the applicability of ICIs for this subpopulation of lung ADC patients.