Tumor microenvironment and signaling pathways in melanoma brain metastasis.

Melanoma has one of the highest propensities to metastasize to the brain, and despite major advances with immune checkpoint inhibitors, brain metastases remain a leading cause of morbidity and mortality. The biological mechanisms governing brain colonization, immune evasion, and resistance to therapy are incompletely understood. This review summarizes recent advances in the understanding of the tumor microenvironment and signaling pathways involved in melanoma brain metastasis, with emphasis on mechanisms that may provide novel therapeutic opportunities. We performed a review of preclinical and clinical studies investigating molecular pathways, immune-cell interactions, and metabolic programs associated with melanoma brain metastasis and response to immunotherapy. Emerging evidence identifies enhancer of zeste homolog 2 (EZH2) phosphorylation by Src kinase as a key driver of brain metastasis through granulocyte colony-stimulating factor (G-CSF) production and recruitment of immunosuppressive neutrophils. Microglia and tumor-associated macrophages constitute major components of the brain metastatic microenvironment and actively support tumor progression. Spleen tyrosine kinase (Syk) signaling contributes to microglial activation and immune-related neurotoxicity during anti-programmed death 1 (PD-1) therapy. Mitochondrial dysfunction, including alterations in mitochondrial contact site and cristae organizing system (MICOS) complex components such as Mic19 and Mic60, promotes innate immune signaling through cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) and TANK-binding kinase 1 (TBK1). TBK1 emerges as a central regulator linking neuroinflammation, microglial activation, metastatic progression, and therapeutic resistance. In addition, metabolic reprogramming mediated by tectonic family member 1 (TCTN1) and carnitine palmitoyltransferase 1A (CPT1A) enhances fatty acid oxidation and promotes melanoma metastasis. These pathways may represent actionable targets that complement immune checkpoint blockade. Melanoma brain metastasis is driven by complex interactions between tumor cells, neutrophils, microglia, and mitochondrial signaling networks. Src-EZH2, TBK1-dependent inflammatory pathways, and TCTN1/CPT1A-mediated metabolic reprogramming are emerging biomarkers and therapeutic targets. Integrating these approaches with anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) therapies may improve disease control, overcome resistance, and reduce immune-related adverse events in patients with melanoma brain metastases.