Targeting the neuro-immune crosstalk in breast cancer brain metastases.

Breast cancer brain metastasis (BCBrM) remains one of the most lethal manifestations of breast cancer. Its response to immunotherapy is severely limited by the blood-brain barrier, which restricts immune cell infiltration and antigen presentation, thereby creating an immunosuppressive microenvironment. To overcome these barriers, recent studies have focused on novel immune checkpoints, including the Lymphocyte-Activated Gene 3-Galectin 3 (LAG3-LGALS3) and T-Cell Immunoreceptor with Ig and ITIM Domains-Nectin Cell Adhesion Molecule 2 (TIGIT-NECTIN2) axes, as well as on the reprogrammed metastatic ecosystem driven by immunosuppressive cells such as Forkhead Box P3-positive (FOXP3⁺) Regulatory T (Treg) cells, Lysosomal-Associated Membrane Protein 3-positive (LAMP3⁺) tolerogenic dendritic cells (DCs), C-C Motif Chemokine Ligand 18-positive (CCL18⁺) M2-like macrophages, Regulator of G-Protein Signaling 5-positive (RGS5⁺) cancer-associated fibroblasts (CAFs), Galectin 1-positive (LGALS1⁺) and TANK-Binding Kinase 1-positive (TBK1⁺) microglia, and phosphorylated Signal Transducer and Activator of Transcription 3-positive (pSTAT3⁺) reactive astrocytes. In addition, targeted inhibition of tumor-derived N-acetyltransferase 8-like (NAT8L) and metabolites N-Acetylaspartate (NAA), suppression of the N-Methyl-D-Aspartate Receptor (NMDAR) signaling pathway in tumor cells, and interventions against γ-Aminobutyric Acid (GABA)ergic reprogramming in BCBrM cells. Moreover, targeted interventions against distinct immune escape pathways-such as the Ubiquitin-Conjugating Enzyme E2T (UBE2T)/Cell Division Cycle 42 (CDC42)/Cluster of Differentiation 276 (CD276) and C-C Motif Chemokine Ligand 2-C-C Motif Chemokine Receptor 2/C-C Motif Chemokine Receptor 4 (CCL2-CCR2/CCR4) axes-have shown promise in reshaping the immune microenvironment and enhancing the efficacy of conventional immunotherapy. Collectively, this perspective outlines evolving strategies in immune checkpoint modulation, cellular ecosystem reprogramming, and neuroimmune intervention, providing a forward-looking framework to enhance the efficacy of immunotherapy in BCBrM.