Targeting the Tumor Microenvironment in EGFR-Mutant Lung Cancer: Opportunities and Challenges

Tyrosine kinase inhibitors (TKIs) have transformed the treatment of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer. However, treatment resistance remains a major challenge in clinical practice. The tumor microenvironment (TME) is a complex system composed of tumor cells, immune and non-immune cells, and non-cellular components. Evidence indicates that dynamic changes in TME during TKI treatment are associated with the development of resistance. Research has focused on identifying how each component of the TME interacts with tumors and TKIs to understand therapeutic targets that could address TKI resistance. In this review, we describe how TME components, such as immune cells, fibroblasts, blood vessels, immune checkpoint proteins, and cytokines, interact with EGFR-mutant tumors and how they can promote resistance to TKIs. Furthermore, we discuss potential strategies targeting TME as a novel therapeutic approach.