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Page 4 of 20 Choi et al. Cancer Drug Resist. 2026;9:12

THE GLYMPHATIC SYSTEM AND ITS IMPLICATION FOR BRAIN TUMORS
Ma et al. studied reduced CSF drainage in GL261 glioma-bearing mouse models using magnetic resonance
imaging (MRI) and dynamic near-infrared (NIR) imaging . The initial expectation was the opposite - that
[32]
brain edema and intracranial hypertension in glioma patients would accelerate CSF drainage due to
increased pressure. However, contrast-enhanced MRI and NIR imaging following cisterna magna injection
showed that CSF circulation was markedly suppressed in glioma models, with tracer signal retained at the
injection site rather than diffusing into the subarachnoid spaces or the basal regions around the Circle of
Willis [Figure 2A]. CSF drainage into systemic blood circulation and cervical lymph nodes were substantially
delayed and decreased, and perineural drainage along the optic nerves - observed using a macromolecular
MRI tracer (Gadospin D, 17 kDa) - showed persistent tracer retention, indicating impaired drainage in
glioma. Instead of normal glymphatic outflow, the study suggested that CSF drainage was redirected through
the spinal cord in glioma.

Toh and Siow investigated alterations in glymphatic flow in glioma patients using the diffusion tensor
imaging (DTI) analysis along the perivascular space (ALPS) . ALPS reflects the diffusivity of perivascular
[31]
CSF flow in the left-right direction, normalized by diffusivity along projection and association fibers, and is
widely used to evaluate glymphatic function. This study analyzed 201 glioma patients (grades II-IV) by
examining preoperative DTI-derived ALPS indices, isocitrate dehydrogenase 1 (IDH1) mutation status, and
peritumoral edema or tumor volumes. The ALPS index was significantly lower in grade IV vs. grades II-III,
and in IDH1 wild-type vs. mutant gliomas, suggesting an association between impaired glymphatic flow and
tumor aggressiveness. In addition, the ALPS index inversely correlated with peritumoral edema volume,
indicating imbalanced CSF influx and efflux in gliomas.

Xu et al. analyzed factors contributing to reduced glymphatic outflow in glioma, which may limit the
drug-delivery efficiency during intrathecal treatment . Common glioma-related complications - such as
[44]
brain edema and elevated intracranial pressure - may hinder therapeutic penetration into tumors, along with
the restrictive BBB and blood-tumor barrier (BTB). Imbalanced CSF production and drainage may also
contribute, due to reduced astrocytic AQP4 expression, a key regulator of water transport [45-47] . Their study
used six-week-old male Sprague-Dawley rats injected with C6 glioma cells in the right striatum, measuring
intracranial pressure, CSF flow dynamics via T1-weighted MRI, ex vivo glymphatic mapping using cisterna
magna injection of Evans Blue, and histological imaging of AQP4 distribution. Intracranial pressure in the
glioma group was nearly doubled, and MRI T1 signals were significantly lower in the tumor-bearing region.
Evans Blue imaging confirmed globally reduced glymphatic transport, especially in the pineal recess and
ventral regions near the Circle of Willis [Figure 2B]. Immunofluorescence showed reduced alpha-smooth
muscle actin (α-SMA) expression and increased cluster of designation 34 (CD34)-positive vessels, indicating
vascular immaturity. Reduced AQP4 and CD34 α-SMA veins were also observed in the tumor region,
+
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suggesting impaired CSF drainage [Figure 2C].
Given such observations, augmenting glymphatic flow may be a key strategy for overcoming the
drug-delivery resistance of brain tumors [48-50] . Enhanced CSF drainage could alleviate intracranial
hypertension and edema, thereby facilitating the transport of immune cells as well as exogenous
chemotherapeutics into tumors. Furthermore, glymphatic-flow augmentation may provide new therapeutic
opportunities for brain tumors, either by leveraging intrathecal administration to bypass BBB/BTB
limitations or by improving CSF–ISF exchange dynamics.

MODULATION METHODS FOR GLYMPHATIC FLOW AUGMENTATION
Various external stimulation modalities - optical, electromagnetic, and mechanical - have been reported to
alter glymphatic flow. Optical approaches include visible sensory stimulation using frequency-modulated

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