Mol Biomed. 2026 Mar 30;7(1):40. doi: 10.1186/s43556-026-00439-y.
ABSTRACT
Astrocytes are increasingly recognized as active regulators of glioma progression rather than passive bystanders. In addition to blood-brain barrier support, metabolic homeostasis, and synaptic regulation, astrocytes undergo state transitions in response to tumor-derived cues, immune inflammation, and therapy-induced stress. We synthesize evidence from single-cell and single-nucleus transcriptomics, spatial transcriptomics, proteomics, and multiplex imaging to delineate major tumor-associated astrocyte programs across perivascular, invasive-margin, and hypoxic niches. Mechanistically, we highlight how convergent signaling networks, including interleukin-6 (IL-6) family signal transducer and activator of transcription 3 (STAT3), nuclear factor-kappa B (NF-κB), interferon, and transforming growth factor-beta (TGF-β) pathways, couple to metabolic rewiring and chromatin reinforcement to stabilize pro-tumor phenotypes and define molecular inflection points during disease evolution. We propose a 4D spatiotemporal mapping framework that integrates staged sampling with spatially resolved readouts to reconstruct astrocyte trajectories and predict therapy-induced state shifts. To accelerate translation, we separate tumor-derived analytes from astrocyte-derived response analytes within a glial liquid biopsy concept, emphasizing extracellular vesicles, cell-free nucleic acids, and state-linked protein signatures. Finally, we discuss state-aware interventions, spanning pharmacologic modulation and gene therapy, with an emphasis on implementable RNA therapeutics such as small interfering RNA (siRNA)lipid nanoparticles and central nervous system (CNS)-appropriate delivery routes, to restore protective barrier functions while limiting immune exclusion and invasion. We outline endpoint panels for in vivo validation and patient stratification, and identify priorities for clinical translation, including longitudinal sampling, spatial atlases, and combinations of astrocyte normalization with immunotherapy and radiotherapy.
PMID:41910655 | DOI:10.1186/s43556-026-00439-y