The neuro–immune–vascular landscape of lung cancer brain metastasis: insights from organoid models

Abstract

Lung cancer brain metastasis (LCBM) is a major cause of cancer-related mortality, driven by the restrictive blood–brain barrier (BBB), an immunosuppressive microenvironment, and dynamic metabolic reprogramming. Increasing evidence suggests that LCBM is governed by coordinated interactions among neural, immune, and vascular components that regulate metastatic colonization, progression, and immune evasion. However, conventional models fail to recapitulate this multicellular, spatially organized ecosystem, limiting mechanistic understanding. Recent advances in organoid technology provide a new paradigm for modeling LCBM. Integrative platforms, including cerebral organoid assembloids, vascularized microfluidic systems, and BBB models, enable reconstruction of key components and dynamic interactions within the brain metastatic niche. These systems have uncovered critical regulatory axes, such as astrocyte-driven colonization, neurovascular remodeling, and metabolic–immune coupling. Beyond structural modeling, organoid platforms enable functional interrogation of patient-specific therapeutic responses in physiologically relevant contexts, facilitating drug sensitivity testing, immunotherapy optimization, and multi-modal treatment modeling. Despite current limitations, organoid-based models provide a critical framework for dissecting the neuro–immune–vascular landscape of LCBM and bridging mechanistic insights with clinical translation, offering new opportunities for therapeutic innovation and personalized treatment.