Abstract: Brain metastasis is a common complication in the progression of multiple solid tumors and is associated with poor prognosis. Its occurrence is not determined solely by the intrinsic invasiveness of tumor cells. After tumor cells enter the central nervous system (CNS), their survival and expansion largely depend on the brain microenvironment. Circulating tumor cells (CTCs) must first cross the blood-brain barrier (BBB). They then encounter a defensive microenvironment centered on reactive astrocytes and disease-associated microglia. This “colonization bottleneck” prevents most disseminated cells from surviving. Under tumor-derived stimulation, neuroglial cells undergo functional reprogramming. They shift from a predominantly restrictive state to a tumor-supportive adaptive state. This shift involves amplified inflammation, enhanced immunosuppression, and altered metabolic coupling, which together reshape the metastatic niche in the brain. At the same time, disruption of microenvironmental homeostasis affects neuronal survival. This links brain metastasis with neuronal injury. Opioid receptors (ORs) are functionally expressed in astrocytes and microglia. Their activation regulates inflammatory responses, metabolic states, and immune signaling networks. They may serve as key signaling nodes that control functional shifts in neuroglial cells. Opioid receptor signaling does not directly drive tumorigenesis. Instead, it likely resets how neuroglial cells respond to external perturbations. This process amplifies brain microenvironmental dysregulation. As a result, it indirectly promotes brain metastatic colonization and aggravates neuronal injury. In summary, brain metastasis results from long-term interactions between tumor cells and the brain microenvironment. Elucidating glia-mediated selection mechanisms and their regulatory nodes will deepen the understanding of the biological nature of brain metastasis. Keywords: brain metastasis, astrocytes and microglia, microenvironmental dysregulation, opioid receptor signaling, neural injury
Cui et al. (Fri,) studied this question.