The review begins with one of the most striking discoveries in modern cancer neuroscience: metastatic tumor cells do not merely tolerate the brain, they actively mimic it. When patient-derived breast and lung cancer cells come into contact with neurons, they upregulate genes associated with synaptic activity and plasticity, including CNR1, EGR2 and ARC. They also increase shuttling of SNAP25, a core component of the SNARE complex that mediates neurotransmitter release, essentially equipping themselves with the molecular machinery neurons use to communicate. This neuronal-like transformation is not limited to breast cancer; single-cell RNA sequencing of patient samples has identified similar neural gene programs in melanoma and non-small cell lung cancer brain metastases, and remarkably, some of these programs resemble those found in glioma cells, suggesting convergent evolutionary strategies for surviving in neural tissue.

The functional consequences of this mimicry are profound. Brain metastatic cells exploit the brain’s neurotransmitter economy for their own growth. In breast cancer cells, exposure to the brain microenvironment induces uptake of gamma-aminobutyric acid through elevated expression of multiple GABA transporters, and the enzyme GABA transaminase then channels this GABA through the GABA shunt into the citric acid cycle, providing metabolic fuel for proliferation. Glutamate, the brain’s principal excitatory neurotransmitter, is similarly co-opted. Triple-negative and basal-like breast tumors express N-methyl-D-aspartate receptor subunits, with phosphorylated GluN2B enriched in brain metastases compared to primary tumors. These receptors allow tumor cells to form pseudo-tripartite synapses with neurons, analogous to how perisynaptic astrocytes interface with synaptic junctions, and NMDA receptor signaling then promotes tumor cell invasion through calcium-dependent kinase pathways.

This metabolic dependency on neurotransmitters creates unexpected therapeutic openings. Because brain metastatic cells rely on GABA processing through GABA transaminase, drugs that inhibit this enzyme block a critical metabolic pathway. Valproic acid and vigabatrin, both established anticonvulsants, have demonstrated efficacy against brain metastasis xenografts by precisely this mechanism. Preclinical studies have also shown that certain antipsychotics, including trifluoperazine, fluphenazine, clozapine and sertindole, suppress proliferation and viability of melanoma and breast cancer brain metastatic cells, though the exact relationship between their cytotoxic effects and the neuronal-like phenotype of these tumors remains to be clarified. Beyond classical neurotransmitters, the review highlights how fasting-induced ghrelin crosses the blood-brain barrier and stimulates neuronal release of neuropeptide Y, which then acts on Y5 receptors on tumor cells to trigger a metabolic switch toward fatty acid oxidation, providing a potential explanation for why underweight lung cancer patients face elevated brain metastasis risk.

Astrocytes, the most abundant glial cells in the central nervous system, emerge from the review as profoundly ambivalent actors. In the earliest stages of metastatic seeding, they may actively resist tumor invasion by secreting plasminogen activator, which generates plasmin to kill incoming cancer cells. Tumor cells counter this defense by expressing plasminogen activator inhibitory serpins. Astrocytes can also induce a state of dormancy in metastatic cells through two distinct mechanisms: deposition of the extracellular matrix glycoprotein laminin-211, which sequesters the transcription factor YAP away from the nucleus and suppresses proliferation, and inhibition of DNA methyltransferase 1, which triggers epigenetic changes that push tumor cells into quiescence. This dormancy phase is considered a rate-limiting step in metastatic development, meaning astrocytes may temporarily contain disease before conditions permit explosive outgrowth.

Once lesions are established, however, the astrocyte-tumor relationship turns decisively pro-tumor. A subpopulation of reactive astrocytes marked by phosphorylated STAT3 co-localizes with brain metastatic cells and secretes a cocktail of immunosuppressive factors including vascular endothelial growth factor A, tissue inhibitor of metalloproteinases-1 and lipocalin-2, alongside extracellular matrix components such as nidogen-2 and neurocan that form physical barriers excluding CD8-positive T-lymphocytes. TIMP-1 in this secretome binds CD63 on T-lymphocytes, reducing expression of cytotoxicity genes through ERK 1/2 signaling and impairing tumor cell killing. This discovery underpins ongoing clinical testing of silibinin, a STAT3 inhibitor, in combination with immune checkpoint blockade, building on an active phase 2 trial of silibinin monotherapy in resected lung and breast cancer brain metastases. Astrocytes also communicate with tumor cells through connexin 43 gap junctions, transferring calcium away from cancer cells to confer chemotherapy resistance, and shuttling the second messenger cGAMP to activate STING signaling in astrocytes, which then release interferon-alpha and tumor necrosis factor that paradoxically enhance tumor cell survival through STAT1 and NF-kappaB pathways.

Tumor-associated macrophages, comprising both resident microglia and bone marrow-derived monocyte macrophages recruited from the periphery, represent another pillar of the brain metastatic microenvironment. Primary breast tumors can prepare the brain for colonization before cancer cells ever arrive, secreting cyclooxygenase-2 and prostaglandin E2 to draw CD11b-positive myeloid cells across the blood-brain barrier and establish what researchers call premetastatic soil. Once inside, these myeloid cells produce S100A8 and S100A9 proteins that recruit additional immune cells and attract tumor cells. Single-cell RNA sequencing has revealed that tumor-associated macrophages exist along a dynamic differentiation continuum, transitioning from APOE-positive states with strong antigen-presentation capacity toward S100A8-positive states resembling myeloid-derived suppressor cells, with elevated CXCL8 and reduced human leukocyte antigen expression. This trajectory suggests tumor cells progressively educate macrophages from a predominantly anti-tumor to a pro-tumor phenotype over time. The transition is not absolute, however. Inhibition of colony-stimulating factor 1 receptor with the agent BLZ945 prevents early microglia-tumor interactions and reduces breast tumor growth in mice, implying microglia play tumor-supporting roles even in the earliest colonization phases.

Neutrophils, long overlooked in brain metastasis biology, are now recognized as abundant and functionally diverse infiltrating cells. The neutrophil-to-lymphocyte ratio, measurable from routine blood tests, predicts worse outcomes in patients receiving stereotactic radiosurgery and identifies lung cancer patients at elevated risk of brain metastasis. Within tumors themselves, neutrophils are drawn to perivascular niches by chemokines including CXCL8, CXCL1, CXCL2 and CXCL5, where they release neutrophil extracellular traps that facilitate tumor cell migration and invasion. A newly described pathway reveals how tumor cells recruit immunosuppressive neutrophils: phosphorylation of the chromatin regulator EZH2 by the proto-oncogene c-Src redirects EZH2 to bind RNA polymerase II, upregulating the transcription factor c-Jun and driving granulocyte colony-stimulating factor-dependent recruitment of arginase-1 and PD-L1 expressing neutrophils that suppress CD8-positive T-lymphocyte proliferation. Neutrophil phenotypes also vary dramatically by tumor genotype; in TP53-mutant lung cancer brain metastases, neutrophils undergo metabolic reprogramming toward fatty acid oxidation that generates reactive oxygen species and reinforces immunosuppression, while in kataegic breast cancer lesions with focal hypermutation, neutrophils instead display pro-inflammatory features.

T-lymphocytes infiltrate brain metastases at levels far exceeding those seen in gliomas, and this difference likely explains why immune checkpoint inhibitors such as nivolumab, pembrolizumab and ipilimumab have achieved intracranial response rates in melanoma, renal cell carcinoma and lung cancer that were once considered unattainable. Melanoma brain metastases are the most immune-infiltrated, showing high densities of CD8-positive cells and spatial correlation between PD-1 expression on lymphocytes and PD-L1 on tumor cells, a pattern consistent with an active but exhausted immune microenvironment. Breast cancer brain metastases are relatively less infiltrated, though triple-negative tumors harbor more cytotoxic T-lymphocytes than HER2-positive ones. Intriguingly, recent work shows that the immune cell populations and T-cell receptor sequences found within brain metastases are largely mirrored in the cerebrospinal fluid, opening the possibility that a simple lumbar puncture could serve as a minimally invasive method to identify patients likely to benefit from immunotherapy or to guide T-cell receptor-directed treatments. Natural killer cells, though a minor fraction of the infiltrate, have emerged as unexpected allies; they produce chemokines such as CXCL9 and CXCL16 that facilitate CD8-positive T-cell trafficking, and their absence compromises the efficacy of combined PD-1 and CTLA-4 blockade in melanoma brain metastasis models.

The review concludes that no single cell type in the brain metastatic microenvironment is exclusively friend or foe, and that functional plasticity driven by tumor-intrinsic and extrinsic pressures creates profound heterogeneity both within individual lesions and across different primary tumor types. The authors call for accelerated integration of single-cell RNA sequencing, spatial transcriptomics and proteomic analyses on patient-derived tissues, combined with longitudinal sampling to track how the microenvironment evolves during treatment. They envision a future in which tumor-specific vulnerabilities at the microenvironmental level are identified and exploited in a personalised manner, transforming brain metastases from a uniformly devastating diagnosis into a tractable and individually targeted clinical challenge.