Hormonal and neuronal interactions shaping the brain metastatic microenvironment

Metastatic progression drives the majority of cancer-related fatalities, and involvement of the central nervous system (CNS) poses especially formidable challenges to patients and clinicians. Brain metastases (BrM), commonly originate from lung, breast and melanoma cancers, and carry disproportionately poor outcomes. Although therapeutic advances have extended survival for many extracranial tumors, BrM incidence continues to climb—underscoring critical knowledge gaps in understanding the unique biology of tumor colonization in the CNS. While definitive evidence remains limited, a growing focus on cancer neuroscience—especially regarding hormone dependent cancer cells in the brain—has begun to reveal that factors normally regulated by sex steroids and neurosteroids may similarly influence the specialized metastatic microenvironment in the CNS. Steroid hormones can permeate the blood-brain barrier (BBB) or be synthesized de novo by astrocytes and other CNS-resident cells, potentially influencing processes such as inflammation, synaptic plasticity, and immune surveillance. However, how these hormonal pathways are co-opted by disseminated cancer cells remains unclear. Here, we review the complex hormonal landscape of the adult brain and examine how neuroendocrine–immune interactions, often regulated by sex hormones, may support metastatic growth. We discuss the interplay between systemic hormones, local steroidogenesis, and tumor adaptation to identify novel therapeutic opportunities.