Extracellular vesicles and immune-glial remodeling in lung cancer brain metastasis: potential intersections with exercise-related myokines.

Lung cancer brain metastasis develops through reciprocal interactions between metastatic tumor cells and a brain-specific vascular, glial, and immune microenvironment. Tumor-derived extracellular vesicles (EVs) can participate in this process by altering blood-brain barrier (BBB) properties, influencing brain-directed distribution, and transferring regulatory cargo to endothelial and myeloid recipient cells. This review integrates direct evidence from non-small cell lung cancer (NSCLC) brain or central nervous system metastasis with related lung cancer EV studies, while distinguishing these findings from cross-cancer mechanistic evidence. We first describe the transition from the BBB to the heterogeneous blood-tumor barrier and distinguish the contributions of astrocytes, resident microglia, recruited monocyte-derived macrophages, and T cells. We then examine how defined EV cargo, including lnc-MMP2-2, LINC00482, miR-21, L1CAM, and miR-374a-5p, affects barrier integrity, myeloid state, or brain-metastatic behavior. Myeloid responses are interpreted according to cellular origin and function rather than by a fixed M1/M2 binary. Exercise-related myokines and exerkines are considered separately as a hypothesis-generating systemic layer that could influence tumor-cell EV production, deliver signals through muscle-derived EVs, or alter recipient-cell responsiveness; none of these routes has yet been established as a causal mechanism in lung cancer brain metastasis. Together, current evidence supports a role for EV-mediated vascular and immune/glial communication in lung cancer brain metastasis, while leaving the contribution of exercise-related signals unresolved.