Lung Cancer Brain Metastasis: Brain Microenvironmental Adaptation, Therapeutic Resistance and Translational Strategies

Abstract

ABSTRACT Lung cancer brain metastasis (LCBM) remains one of the most challenging clinical conditions limiting survival and neurological function. The development of LCBM is shaped by continuous exchange of molecular signals between tumor cells and the brain microenvironment, involving blood–brain barrier remodeling, glial and immune reprogramming, neuronal signaling, and metabolic adaptation. Together, these phenomena support brain colonization, immune escape, and therapeutic resistance. The management of LCBM has improved with the advent of stereotactic radiotherapy, targeted therapy, immunotherapy, chemoimmunotherapy, and antibody–drug conjugates. Yet durable intracranial control is still limited by intrinsic barrier heterogeneity, protected residual intracranial disease, and molecular resistance. This review summarizes recent advances in biology, preclinical modeling, therapeutic resistance, and translational treatment strategies of LCBM. By linking brain‐specific metastatic biology with evolving therapeutic approaches, this review provides a framework for understanding LCBM progression and for developing more effective strategies to overcome intracranial resistance.