Brain metastasis from non-small cell lung cancer: crosstalk between cancer cells and tumor microenvironment components

The majority of patients with lung cancer are diagnosed at an advanced stage, with a substantial proportion exhibiting signs of brain metastases (BMs). BM is associated with debilitating symptoms, including headaches, seizures and neurological or cognitive impairments, which severely impact the quality of life of patients. Despite considerable advancements in lung cancer treatment modalities, the management of BM remains challenging due to the complex cellular and structural nature of the blood-brain barrier and resistance driven by acquired genetic mutations. Non-small cell lung cancer (NSCLC) is characterized by diverse genetic alterations. The application of immunotherapy has successfully enhanced antitumor immune responses within the tumor microenvironment (TME) of affected patients. The intricate interplay between NSCLC cells and the TME plays a critical role in the pathogenesis of BM. This review focuses on the brain-specific TME and its exploitation by tumor cells to establish metastases through strategic, site-specific mechanisms. The reciprocal molecular interactions, immune modulation and adaptation of NSCLC cells to the brain metastatic niche are central to this process. A deeper understanding of the complex crosstalk between tumor cells and TME is essential for devising more effective and targeted therapeutic interventions for BM.