Dual immunometabolic regulation and therapeutic targeting of TAMs, microglia and astrocytes in brain metastasis of non-small cell lung cancer.

Brain metastases (BM) from non-small cell lung cancer (NSCLC) significantly contribute to poor prognosis, with their progression intrinsically linked to the unique immune microenvironment of the brain. This review comprehensively examines the dual regulatory roles and underlying mechanisms of three pivotal cell types within the metastatic niche-tumor-associated macrophages (TAMs), microglia, and astrocytes-during brain metastasis development. TAMs promote tumor invasion and the establishment of an immunosuppressive milieu through metabolic regulation and differentiation into functional subtypes, with profiles distinct from those in primary tumors. As resident immune cells of the central nervous system, microglia show marked functional polarization: they can inhibit metastasis by directly targeting tumor cells, cooperating with adaptive immunity, and enhancing radiosensitivity. However, under specific microenvironmental cues, they may also support tumor growth and immune evasion. Similarly, astrocytes transition from a neuroprotective to a tumor-promoting phenotype, driving progression through inflammatory cytokine secretion, gap junction-mediated intercellular communication, metabolic reprogramming, and exosomal signaling. Building on these mechanistic insights, this review further summarizes emerging therapeutic strategies targeting these cell types, including engineered vesicle-mediated TAM reprogramming, nanoparticle-based combination therapies, metabolic checkpoint interventions, and targeted signaling pathway inhibitors. These insights advance the "seed and soil" hypothesis in brain metastasis and support the development of precision therapies targeting the microenvironment to improve outcomes for patients with NSCLC and BM.