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11 November 2025

Glia Between Resistance and Radiotoxicity in Glioblastoma: Mechanisms and Translational Perspectives—A Narrative Review

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1
Unit of Radiation Oncology, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
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Radiation Oncology, Policlinico Umberto I, Department of Radiological, Oncological and Pathological Sciences, “Sapienza” University of Rome, 00185 Rome, Italy
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IRCSS Neuromed, 86077 Pozzilli, Italy
4
Unit of Diagnostic Imaging, Department of Medicine, Surgery and Neurosciences, University of Siena, 53100 Siena, Italy
Neuroglia2025, 6(4), 44;https://doi.org/10.3390/neuroglia6040044
This article belongs to the Special Issue Neuroglia at the Crossroads: Emerging Insights into Neurological Disease Mechanisms
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Abstract

Background: Glioblastoma (GBM) remains refractory to chemoradiotherapy. Glial populations—microglia/monocyte-derived macrophages, reactive astrocytes, and the oligodendrocyte lineage—shape both treatment resistance and radiation-related brain injury. Scope: We synthesize how myeloid ontogeny and plasticity, astrocytic hubs (IL-6/STAT3, TGF-β, connexin-43/gap junctions), and oligodendrocyte precursor cells (OPCs)–linked programs intersect with DNA-damage responses, hypoxia-driven metabolism, and extracellular vesicle signaling to support tumor fitness while predisposing normal brain to radiotoxicity. Translational implications: Convergent, targetable pathways (IL-6/JAK–STAT3, TGF-β, chemokine trafficking, DDR/senescence) enable co-design of radiosensitization and neuroprotection. Pragmatic levers include myeloid reprogramming (CSF-1R, CCR2), astrocyte-axis modulation (STAT3, TGF-β, Cx43), and brain-penetrant DDR inhibition (e.g., ATM inhibitors), paired with delivery strategies that raise intratumoral exposure while sparing healthy tissue (focused-ultrasound blood–brain barrier opening, myeloid-targeted dendrimers; Tumor Treating Fields as an approved adjunct therapy). Biomarker frameworks (TSPO-PET, macrophage-oriented MRI radiomics, extracellular vesicle liquid biopsy) can support selection and pharmacodynamic readouts alongside neurocognitive endpoints. Outlook: Timing-aware combinations around radiotherapy and hippocampal/white-matter sparing offer a near-term roadmap for “glia-informed” precision radiotherapy.

1. Introduction and Rationale

Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults and continues to resist meaningful survival gains despite maximal safe resection followed by radiotherapy with concomitant and adjuvant temozolomide (Stupp protocol). Contemporary cohorts report a median overall survival of 12–16 months, underscoring an unmet need for durable efficacy with current regimens [1,2,3].
Over the past decade, the tumor microenvironment (TME) has emerged as a principal determinant of GBM behavior and therapeutic response. Among TME constituents, glial cells—microglia and monocyte-derived macrophages (collectively tumor-associated macrophages, TAMs), astrocytes, and the oligodendrocyte lineage—exert pervasive effects on growth, invasion, immune evasion, and resistance to radio- and chemotherapy. Single-cell and spatial profiling consistently show that TAMs form a dominant immune compartment and engage in reciprocal signaling with glioma cells that promote immunosuppression, sustain stem-like states, and mitigate treatment-induced stress [4,5].
Microglia and TAMs. TAMs in GBM arise from yolk-sac–derived microglia and infiltrating bone-marrow–derived monocytes. This ontogeny, only partially captured by the historical M1/M2 dichotomy, spans a continuum of activation states. Functionally, TAMs foster tumor progression through cytokine/chemokine networks, metabolic crosstalk, and extracellular vesicles (EVs); they have been directly implicated in therapeutic resistance. Notably, radiotherapy (RT) remodels myeloid populations in ways that may be exploitable: preclinical work indicates that post-RT CSF-1R inhibition can reprogram macrophage-mediated resistance, providing a mechanistic rationale for timing-aware combinations [5,6,7].
Astrocytes. Reactive astrocytes influence GBM trajectory by modulating blood–brain barrier (BBB) permeability, shaping immune ingress/egress, supplying trophic and metabolic support, and exchanging EV cargo with tumor cells. Increasing evidence links astrocyte reactivity to radio- and chemoresistance; recent syntheses highlight targetable hubs at the astrocyte–tumor interface, including IL-6/STAT3 and TGF-β signaling [8,9].
Oligodendrocyte lineage. Oligodendrocyte progenitor cells (OPCs) and oligodendroglia contribute to invasion routes and microenvironmental remodeling. New data suggest that GBM cells hijack neurodevelopmental programs of the oligodendrocyte lineage to enhance infiltration and synaptic coupling with neural circuits—features with implications for both resistance and network dysfunction [10].
The same glial networks that support tumor survival also participate in radiation-induced brain injury and cognitive sequelae in the non-tumor brain. Clinical and preclinical literature converge on a multifactorial pathogenesis for radiation-induced cognitive dysfunction (RICD), in which microglial activation, astrogliosis, white-matter injury/demyelination, oxidative stress, and neuroinflammation interact over time. Recent reviews and mechanistic studies underscore persistent innate immune activation after cranial RT and link maladaptive glial states to synaptic dysfunction and cognitive deficits [11,12,13,14].
These threads motivate a unified framework: glia sit at the crossroads of treatment resistance in tumor tissue and radiotoxicity in healthy brain, with shared mechanisms—cytokine/chemokine networks, EV-mediated signaling, hypoxia-driven metabolic rewiring, and heightened DNA damage response (DDR) activity—that are therapeutically targetable. This convergence reframes resistance not merely as a tumor-intrinsic property but as an emergent, glia-conditioned systems phenotype, suggesting that radiosensitization and neuroprotection should be co-designed rather than pursued as separate aims [15].
From a translational perspective, several avenues are poised for rational combination with standard-of-care RT/temozolomide: myeloid-directed strategies (e.g., CSF-1R inhibition; approaches that reprogram rather than deplete TAMs), astrocyte-axis modulation (e.g., STAT3/TGF-β), and delivery technologies that enhance tumor uptake while limiting normal brain exposure. Although clinical validation remains early, systems and in silico work support the potential of co-targeting microglia/macrophages to augment GBM control [6,9,16]. Finally, advances in circuit-level neuroscience show that high-grade gliomas integrate into and remodel cortical networks, with functional connectivity correlating with survival and language performance. These tumor–circuit interactions likely intersect with glial biology and may inform biomarker strategies—neuroinflammation imaging (18-kDa translocator protein, TSPO-PET), advanced MRI—and exploratory radiomics/radiogenomics frameworks for stratifying efficacy and toxicity risks [17].
This review, therefore, has the following aims:
(1)
To synthesize current knowledge on microglia, astrocytes, and the oligodendrocyte lineage in GBM resistance;
(2)
To integrate evidence on glia-mediated radiotoxicity;
(3)
To outline translational opportunities—including drug targets and trial designs—that jointly pursue tumor control and cognitive preservation.
A conceptual overview linking tumor-side resistance, brain-side radiotoxicity, and translational levers is shown in Figure 1.
Figure 1. Glia between resistance and radiotoxicity in glioblastoma. Abbreviations: AQP4—Aquaporin-4. ATM—Ataxia-Telangiectasia Mutated. BBB—Blood–Brain Barrier. BTB—Blood–Tumor Barrier. C1q—Complement component 1q. C3—Complement component 3. CCR2—C-C chemokine receptor 2. CCL2—C-C motif chemokine ligand 2. CR3—Complement receptor 3. CSF1R—Colony-Stimulating Factor 1 Receptor. DDR—DNA Damage Response. DTI—Diffusion Tensor Imaging. EVs—Extracellular Vesicles. FUS—Focused Ultrasound. GBM—Glioblastoma. HIF-1—Hypoxia-Inducible Factor-1. HVLT-R—Hopkins Verbal Learning Test–Revised. IL-6—Interleukin-6. OPCs—Oligodendrocyte Precursor Cells. PET—Positron Emission Tomography. ROS—Reactive Oxygen Species. STAT3—Signal Transducer and Activator of Transcription 3. TAMs—Tumor-Associated Macrophages. TGF-β—Transforming Growth Factor-beta. TSPO—18-kDa Translocator Protein. WM—White Matter.

2. Microglia in Glioblastoma

TAMs form the dominant immune ecosystem in GBM; below, we move from origins and niches to functional states, communication routes, and therapy-facing implications.

2.1. Ontogeny, Compartments, and Cellular Burden

The GBM myeloid compartment comprises brain-resident microglia and bone-marrow–derived monocytes/macrophages (MDMs) that infiltrate from the periphery. Single-cell and spatial studies delineate transcriptionally distinct lineages with partly distinct spatial topographies: microglia are enriched at the invasive margin, whereas MDMs accumulate within hypoxic cores and at recurrence. Collectively, these populations constitute a dominant immune compartment—often approximately 30–50% of all cells in GBM specimens—underscoring their clinical relevance [5,18,19].

2.2. Beyond M1/M2: A Continuum of Functional States

The historical M1/M2 dichotomy does not capture TAM plasticity in GBM. Single-cell atlases reveal gradients of interferon-responsive, phagocytic, lipid-handling, and immunosuppressive programs that distribute differently across microglia and MDMs and vary by niche and disease stage. Meta-analyses and cytometric profiling demonstrate mixed M1/M2 features within the same tumors, supporting a dynamic, context-dependent myeloid identity rather than polarized endpoints [20,21]. This state continuum sets the stage for how myeloid cells communicate with glioma and glioma stem-like cells (GSCs), shaping niche maintenance and treatment tolerance.

2.3. Crosstalk with Tumor Cells and GSCs: Cytokines, Pathways, and EVs

Bidirectional signaling between glioma cells, glioma stem-like cells (GSCs), and myeloid populations proceeds via cytokines/chemokines (e.g., IL-6, TGF-β), metabolic exchange, and EVs. EVs from GBM and immune cells deliver miRNAs, lipids and proteins that drive immunosuppression, angiogenesis, and TAM reprogramming, maintaining stem-like niches and fostering treatment resistance; EVs are also under evaluation as biomarkers and therapeutic shuttles [22].

2.4. Recruitment and Immune Modulation: CCR2/CCL2 and CX3CR1 Axes

MDM recruitment to GBM is strongly linked to the CCL2-CCR2 axis, with CCL2 produced by tumor and stromal cells. Neutralizing CCL2-CCR2 reduces myeloid influx and improves therapy responses in preclinical models, and elevated CCL2 correlates with worse outcomes. CX3CL1/CX3CR1 signaling—highly relevant to microglia—also shapes TAM localization and function. Together with TGF-β/IL-10 networks, these chemokine circuits support T-cell suppression and immune escape characteristic of GBM [23,24,25].

2.5. Radio- and Chemoresistance: RT-Driven Remodeling and Therapeutic Rationale

Radiotherapy (RT) remodels the myeloid ecosystem in GBM. In landmark preclinical work, RT induced shifts in macrophage populations that could be exploited by CSF-1R inhibition, providing a rationale for post-RT myeloid-directed therapy [26]. Translationally, the CSF-1R inhibitor pexidartinib (PLX3397) added to RT/temozolomide (TMZ) showed feasibility but limited benefit in unselected patients, highlighting the need for biomarker-based stratification and optimized scheduling [27]. Recent multi-omics studies also caution that anti-CSF-1R therapy can elicit a fibrotic, pro-survival niche in glioma models and recurrences—an adaptive program that may blunt monotherapy efficacy and argues for rational co-targeting and temporal sequencing with RT [28]. Together, these observations argue for timing-aware, biomarker-enriched strategies; we next outline practical implications for reprogramming, delivery, and imaging.

2.6. Therapeutic Implications: Reprogramming over Depletion, Delivery, and Imaging

Current data favor reprogramming TAMs (e.g., via CSF-1R, CCR2/CCL2, STAT3, metabolic rewiring) rather than indiscriminate depletion, preserving useful functions while limiting escape circuits. Targeted delivery to myeloid cells may reduce systemic toxicity and increase intratumoral on-target effects: hydroxyl-dendrimer conjugation of the CSF-1R inhibitor BLZ945 selectively accumulates in TAMs, repolarizes immunosuppressive phenotypes, and improves outcomes in orthotopic GBM models—highlighting drug-delivery solutions that could synergize with RT/TMZ [29]. For patient selection and pharmacodynamic (PD) readouts, microglia/TAM-related imaging is advancing. TSPO-PET shows prognostic associations in diffuse gliomas and isocitrate dehydrogenase (IDH)-wild-type GBM and is being evaluated pre-RT as a stratifier; third-generation TSPO tracers may further refine specificity [30,31,32]. In parallel, astrocyte-centered circuits intersect with these myeloid programs and offer complementary targets for glia-informed combinations.

3. Astrocytes and Astrocytic Reactivity

Astrocytes shape GBM biology across reactive states, paracrine hubs, structural niches like BBB/blood–tumor barrier (BTB), and vesicle-mediated communication; below we move from taxonomy to therapeutic implications.

3.1. Reactive States: Beyond A1/A2

Reactive astrocytes undergo morphological, transcriptional, and functional reprogramming in response to CNS injury and disease, and fixed binary categories inadequately capture their diversity across space and time. A 2021 Nature Neuroscience consensus recommends moving beyond “good/bad” or A1/A2 labels toward multidimensional phenotyping with in vivo validation [33]. Still, the classic A1-induction mechanism remains informative: activated microglia can convert astrocytes into a neurotoxic state via IL-1α, TNF, and C1q, a triad necessary and sufficient for A1 transformation [34]. This framework motivates mapping the paracrine astrocyte–tumor loops that sustain malignant phenotypes.

3.2. Paracrine Signaling and Feed-Forward Loops (IL-6/STAT3, TGF-β)

Astrocytes engage in bidirectional communication with glioma and GSCs via cytokines/chemokines, growth factors, and metabolic cues. The IL-6/STAT3 axis is a prototypical feed-forward loop: glioma-derived IL-6 activates STAT3, which upregulates IL-6 in astrocytes; astrocyte-derived IL-6 then further activates STAT3 in tumor cells, promoting proliferation, migration/invasion, and survival [35]. Contemporary syntheses reinforce this hub and outline additional targetable crosstalk (e.g., TGF-β), positioning astrocyte-centered pathways as candidate therapeutic nodes [9]. These signaling convergences set up the role of intercellular connectivity via gap junctions.

3.3. Gap Junctions and Connexin-43 (Cx43): Invasion and Temozolomide Resistance

Astrocyte–glioblastoma gap-junction intercellular communication (GJIC) via Cx43 supports local invasion and contributes to temozolomide resistance. Pharmacologic disruption and repurposing strategies provide consistent preclinical/early-translational evidence of sensitization, but clinical validation in GBM is pending [36,37,38,39,40,41]. These data justify exploratory combinations in carefully selected settings and emphasize attention to delivery constraints and off-target effects. Because much of this interaction occurs at the vascular interface, we next consider astrocytic roles in the BBB/BTB and the perivascular niche.

3.4. BBB/BTB and the Perivascular Niche

Astrocytic endfeet help organize and maintain the BBB; in GBM, barrier remodeling yields a heterogeneous BTB that constrains drug delivery and shapes immune access. State-of-the-art reviews underscore astrocytes’ roles in BBB/BTB structure–function and therapeutic resistance [15,42]. Astrocytic water channels—most notably aquaporin-4 (AQP4)—contribute to gliovascular homeostasis; mislocalization/dysregulation of AQP4 in gliomas has implications for edema, barrier integrity, and perivascular signaling [43,44,45]. Perivascular stromal cells—including pericytes and astrocytes—also provide invasion-permissive cues and vascular remodeling that support GBM growth and treatment tolerance [46]. Beyond humoral and structural factors, extracellular vesicles represent an additional channel for astrocyte reprogramming.

3.5. EVs and Astrocyte Reprogramming

GBM-derived EVs rewire surrounding cells; in astrocytes, GBM-EVs can induce tumor-supportive phenotypes and activate canonical oncogenic pathways (e.g., ERK, PI3K/AKT) [47]. Broader EV literature in gliomas highlights EV-driven immune suppression and STAT3 activation, providing a mechanistic bridge between astrocyte reactivity and microenvironmental immune escape; EVs are also being developed as biomarkers and delivery vehicles [48,49]. These mechanistic nodes nominate actionable targets and highlight delivery needs to achieve effective astrocyte-directed therapy.

3.6. Therapeutic Implications

Actionable targets within astrocyte-centered networks include: IL-6/STAT3 (JAK–STAT inhibitors, context-specific strategies), TGF-β modulators, and Cx43/GJIC disruption to blunt invasion and sensitize to temozolomide. A recent comprehensive review details these opportunities and emphasizes biomarker-informed, timing-aware combinations alongside RT/TMZ [9]. Given BBB/BTB constraints, device-assisted BBB modulation may be required to realize astrocyte-targeting strategies clinically [42]. The next section examines the oligodendrocyte lineage, which intersects these axes through OPC-like programs and neural network–linked invasion.

4. Oligodendrocyte Lineage and Tumor Progression

The oligodendroglial axis links malignant cell states to neural circuit engagement and invasion; below, we move from state taxonomy to mechanisms and translational levers.

4.1. OPC-like Tumor Cell States in GBM

Single-cell atlases established that GBM malignant cells occupy four recurrent programs—oligodendrocyte progenitor cell–like (OPC-like), neural progenitor cell–like (NPC-like), mesenchymal-like (MES-like), and astrocyte-like (AC-like)—with substantial plasticity across niches and time. The OPC-like program (OLIG2/PDGFRA-associated) is a stable component of this landscape and can be favored by specific genetic drivers (e.g., PDGFRA amplification) [50,51]. Recent spatial and epigenetic analyses refine this view: tumors with a “high-neural” signature show enrichment of OPC/NPC/AC-like states, increased neuron–glioma synaptogenesis, and worse outcome, supporting a link between neural-lineage programs and invasive, therapy-tolerant behavior [52]. These lineage programs intersect with neuronal activity, motivating a focus on circuit-coupled invasion.

4.2. OPC Programs, Invasion, and Neuronal Mechanisms

Work from “cancer neuroscience” demonstrates that high-grade gliomas integrate into neural circuits through glutamatergic synapses and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)–dependent currents, and that neuronal activity accelerates glioma growth and spread [53,54]. Building on this, in vivo imaging and modeling show that OPC/NPC-like glioma subpopulations are prominent in invasion, co-opting neurodevelopmental programs and neuron-derived cues to migrate along physiological scaffolds [55]. A 2022–2024 body of work further details how glioblastoma hijacks neuronal mechanisms to drive brain invasion, extending the original synaptic findings and tying them to state-specific motility [56,57]. Because these migratory routes often follow axon-rich highways, the white matter emerges as a context-dependent niche.

4.3. White Matter as a Context-Dependent Niche

GBM cells frequently migrate along myelinated white-matter tracts, using axonal pathways and perivascular routes as highways for spread [57]. Interestingly, white matter can also exert pro-differentiative pressure: in a human tissue–based model, contact with white matter induced a pre-oligodendrocyte fate via SOX10 upregulation, concomitantly reducing proliferation and invasion—a tumor-suppressive feedback to injury [58]. Together, these data suggest dual behavior: structural guidance and neuron-driven signals facilitate OPC/NPC-like invasion, while specific white-matter cues can push toward oligodendroglial differentiation and relative quiescence—an axis potentially exploitable by pro-differentiation strategies. This dualism points to upstream developmental regulators that bias state and motility.

4.4. Developmental Transcription Factors of the Oligodendroglial Lineage in GBM

The developmental basic helix–loop–helix (bHLH) factors ASCL1 and OLIG2 cooperate to shape GBM cell identity and motility. Genetic and single-cell perturbation studies show that these transcription factors (TFs) drive tumor initiation, co-regulate OPC- versus neural stem cell (NSC)/astrocyte-like programs, and tune migration; high ASCL1 favors a highly migratory NSC/astrocyte-like phenotype, whereas OLIG2 biases toward OPC-like states [59]. These findings dovetail with the OPC-like state described by Neftel et al. and with epigenetic data linking OPC programs to synaptic integration and invasion [50,52]. Given the lineage’s role in myelination, we next consider how tumor–myelin interactions contribute to disease biology.

4.5. Intersections with Myelin Biology

Beyond malignant programs, the oligodendrocyte/OPC compartment is altered in and around GBM. Reviews synthesizing neuron–oligodendroglial interactions highlight that glioma-driven network remodeling likely perturbs myelin homeostasis, with consequences for conduction, plasticity, and invasion routes along axon-rich tracts [60]. Clinically, diffusion imaging underscores the vulnerability of white-matter integrity in diffuse gliomas, reinforcing the biological and functional footprint of tumor–myelin interactions [61]. These insights nominate state-aware and niche-aware strategies for translation.

4.6. Translational Implications

State-aware targeting. The oligodendroglial axis nominates OLIG2/ASCL1-linked programs and PDGFRA-dependent signaling as actionable nodes; however, direct OLIG2 inhibitors are not yet clinically available, arguing for downstream/pathway targeting and timed combinations with RT/TMZ [59].
Pro-differentiation strategies. The white-matter induced SOX10 program suggests that differentiation-biased interventions could restrain invasion in selected contexts; careful patient/state selection will be essential given the dualistic white-matter effects [58].
Circuit-level therapies. Given the coupling between neuron–glioma synapses and OPC/NPC-like invasion, emerging approaches that dampen synaptogenic signaling or activity-regulated trophic loops (e.g., neuroligin-3 (NLGN3)/brain-derived neurotrophic factor (BDNF) pathways) may complement standard chemoradiotherapy [52,54].
The next section integrates these lineage themes with shared mechanisms of resistance and radiotoxicity across glial compartments.

5. Shared Mechanisms of Resistance and Radiotoxicity

Tumor resistance and normal brain toxicity converge on common glial programs; below, we align inflammatory, metabolic, and DNA damage/senescence axes across contexts.

5.1. Inflammation, Cytokine Networks, and EVs

Convergent inflammatory programs link GBM treatment resistance with radiation-induced normal brain injury. Within tumors, myeloid and astroglial circuits centered on IL-6/JAK–STAT3 and TGF-β drive immune suppression, stemness, invasion, and treatment tolerance; astrocytes and tumor cells engage in feed-forward IL-6↔STAT3 signaling that reinforces malignant phenotypes [9,35]. Irradiation of normal brain tissue also provokes innate immune activation with microglial and astrocytic responses, BBB disruption, and chronic neuroinflammation, all implicated in radiation-induced cognitive dysfunction (RICD) [12,62]. Complement signaling provides a mechanistic bridge between the two contexts: in murine models, glia-selective deletion of C1q prevents irradiation-induced synaptic loss and cognitive deficits [63], consistent with broader literature on complement-mediated synaptic pruning [64].
Across tumor and peritumoral tissue, EVs orchestrate intercellular communication, carrying miRNAs/proteins that reprogram recipient cells, promote immunosuppression/angiogenesis, and propagate resistance states; EVs are also emerging as biomarkers and therapeutic shuttles able to cross the BBB [65]. These inflammatory and EV-mediated pathways interface closely with metabolic rewiring and hypoxia.

5.2. Metabolic Rewiring and Hypoxia

Hypoxia—pervasive in GBM—promotes radio- and chemoresistance via HIF-1–driven programs that rewire metabolism, enhance angiogenesis, and sustain immunosuppression; multiple recent reviews confirm HIF-1 associations with poor outcome and treatment resistance [66,67,68]. Metabolism also underpins glia–tumor coupling. GBM cells co-opt neuron–glia metabolic partitioning (e.g., astrocytic lactate supply), and lactate-dependent histone lactylation has been shown to epigenetically reprogram GBM cells toward immune-evasive states (upregulating CD47) with contributions from both GSCs and myeloid cells [69,70]. In the normal brain, RT perturbs glial metabolism and synaptic homeostasis; microglial activation and astrocytic dysfunction contribute to synaptic loss and white-matter injury underlying cognitive deficits, with durable alterations of microglial dynamics after cranial RT [13,71].
An emergent tumor-intrinsic node linking lipid metabolism to radioresistance is TMEM164. In radioresistant GBM models, TMEM164 functionally cooperates with fatty-acid synthase (FASN) to sustain NADPH availability and limit radiation-induced reactive oxygen species (ROS), thereby suppressing necroptosis. TMEM164 knockdown increases ROS burden and restores radiosensitivity, nominating a TMEM164–FASN–NADPH–ROS axis as a metabolic handle alongside hypoxia-driven rewiring. Clinically, brain-penetrant FASN inhibition (e.g., denifanstat/TVB-2640) has shown feasibility and response signals with bevacizumab in recurrent high-grade astrocytoma (HGA), supporting exploration of RT-timed, biomarker-enriched combinations that leverage lipid/redox vulnerabilities [72,73]. Metabolic stress and hypoxia intersect with DDR and therapy-induced senescence, which we consider next.

5.3. DNA Damage Response and Therapy-Induced Senescence

On the tumor side, upregulated DDR pathways—ataxia-telangiectasia mutated (ATM), ATM and Rad3-related (ATR), DNA-dependent protein kinase catalytic subunit (DNA-PKcs), and poly(ADP-ribose) polymerase (PARP)-dependent repair—are central to radio-chemoresistance. Brain-penetrant DDR inhibitors are entering the clinic: the ATM inhibitor AZD1390 shows favorable CNS pharmacology and preliminary safety with RT; antitumor activity in GBM remains to be defined [74,75]. In parallel, RT provokes therapy-induced senescence (TIS) and a senescence-associated secretory phenotype (SASP) in non-neoplastic brain cells—particularly astrocytes—creating a cytokine-rich, receptor tyrosine kinase–activating milieu that accelerates GBM regrowth after therapy. Eliminating RT-induced senescent cells or dampening SASP attenuates recurrence in preclinical models and may also mitigate cognitive toxicity, suggesting that senolytic/SASP-modulating strategies could decouple tumor control from neurotoxicity when timed with RT [76,77,78,79].
Synthesis and translational implications.
  • Inflammation modules (IL-6/STAT3, complement), metabolic stress (hypoxia/lactate), and DDR/TIS form an interconnected scaffold that shields tumor cells from RT/TMZ and drives RT-related glial dysfunction and cognitive injury [35,66,76].
  • EVs can be leveraged as biomarkers and as delivery vehicles for radiosensitizers or neuroprotectants across the BBB [65].
  • Early clinical progress with brain-penetrant DDR inhibitors (e.g., AZD1390) and preclinical evidence for senescence-targeting interventions motivate trials integrating myeloid/astrocyte reprogramming, DDR modulation, and SASP control, with neurocognitive endpoints and glia-inflammation imaging to monitor on-target effects [74,76].
We next examine radiotoxicity mechanisms in the non-tumor brain that mirror—and potentially can be co-managed with—these tumor-facing programs.

6. Glia and Radiotoxicity in Healthy Brain Tissue

Glial responses orchestrate radiation-related network injury; below, we move from mechanisms to mitigation.

6.1. Mechanistic Overview and Clinical Relevance

RICD is a multifactorial syndrome in which glial responses—particularly microglial activation and astrocytic reactivity—intersect with vascular injury, synaptic loss, impaired hippocampal neurogenesis, and white-matter damage. Contemporary syntheses converge on neuroinflammation and oxidative stress as early triggers that propagate to long-term network dysfunction and cognitive deficits [11]. Within this framework, microglia–complement signaling emerges as a central driver of synaptic pathology.

6.2. Microglia, Complement Signaling, and Synaptic Dysfunction

After cranial irradiation, microglia shift from homeostatic surveillance toward pro-inflammatory states, with persistent alterations in motility and territory maintenance observed for weeks in vivo. Activated microglia and the complement cascade (C1q→C3→CR3) tag and remove synapses, driving dendritic spine loss and memory decline. Causality is supported by glia-selective C1q deletion preventing irradiation-induced microglial activation, synaptic loss, and cognitive impairment, and CR3 dependence of irradiation-mediated spine loss in male mice, with emerging pharmacologic CR3 modulation as a candidate neuroprotective approach [63,71,80,81]. Astrocytes act in parallel, contributing to BBB/BTB dysfunction and network effects.

6.3. Astrocytes, BBB/BTB Disruption, and Network Effects

Astrocytic gliosis accompanies microglial activation and contributes to cytokine amplification (e.g., IL-1α/TNF signaling), glutamate dysregulation, and BBB/BTB remodeling. Radiation-associated chronic inflammation has been linked to microglial phagocytosis of astrocyte endfeet and BBB impairment, connecting glial responses to vascular leak, white-matter edema, and impaired homeostasis, with downstream effects on synaptic plasticity and cognition [82]. Parallel vulnerabilities are evident in neurogenic niches.

6.4. Hippocampal Neurogenesis and Memory

The dentate gyrus is exquisitely radiosensitive. Foundational studies demonstrated that cranial irradiation suppresses postnatal/adult hippocampal neurogenesis and that reduced neurogenesis correlates with spatial memory deficits. Subsequent work refined dose–response relationships and the susceptibility of neural stem/progenitor subpopulations, indicating that even clinically relevant doses can durably perturb neurogenic niches. In parallel, clinical strategies that spare or pharmacologically protect the hippocampi—such as hippocampal-avoidance whole-brain RT combined with memantine—preserve cognitive trajectories without compromising intracranial control in appropriate indications. Together, these data support a model in which early radiation injury to the neurogenic lineage sets the stage for later network dysfunction, providing a mechanistic rationale for hippocampal sparing and adjunct neuroprotectants [83,84].

6.5. Oligodendrocytes, OPCs, and White-Matter Injury

Radiation damages oligodendrocytes and OPCs, leading to demyelination, conduction abnormalities, and white-matter necrosis in severe cases. Recent reviews emphasize OPC loss as a key event linking white-matter injury to cognitive dysfunction, consistent with diffusion-MRI studies showing degradation of long association tracts after cranial RT [85,86]. Temporal dynamics help identify intervention windows.

6.6. Time Course: From Acute Inflammation to Delayed Cognitive Decline

Cranial RT triggers a biphasic cascade. Within hours to days, innate immune activation emerges—microglia shift from surveillance to pro-inflammatory states, astrocytes upregulate reactive programs, and BBB integrity is perturbed. Over weeks to months, these early cues translate into synaptic loss (via complement-mediated pruning) and white-matter injury/demyelination that track with cognitive decline. This temporal dissociation indicates actionable windows: early modulation of glial activation (e.g., complement/microglial pathways) to preserve synapses, and longer-term strategies to protect or restore hippocampal neurogenesis and myelin [71]. These insights inform evidence-based mitigation strategies.

6.7. Evidence-Based Mitigation Strategies

Two clinically validated strategies reduce RICD risk in appropriate indications:
  • Hippocampal-avoidance whole-brain radiotherapy (HA-WBRT) + memantine. In the phase III NRG-CC001 trial, HA-WBRT with memantine better preserved cognitive function and patient-reported outcomes without compromising intracranial control or survival, confirming earlier phase II findings (RTOG 0933) [87,88].
  • Ultra-high-dose-rate (FLASH) radiotherapy (preclinical). Multiple mouse studies report long-term preservation of learning and memory after whole-brain FLASH vs. conventional dose-rate RT, accompanied by less hippocampal spine loss and neuroinflammation [89,90,91,92].
Additional experimental avenues include complement inhibition (C1q/C3/CR3 axis) and targeted microglial modulation, which have shown synapse- and cognition-sparing effects in rodent models of cranial irradiation but await clinical testing [63,81]. Translational sections below build on these guardrails to propose glia-informed combinations with RT.

7. Translational Opportunities

We outline targetable glial axes, delivery strategies, and biomarkers to operationalize “glia-informed” RT. Key glia-targeted strategies and representative agents are summarized in Table 1.
Table 1. Glia-informed targets and candidate interventions for GBM radiotherapy.

7.1. Targetable Glial Axes for Combination with Radiotherapy

CSF-1R (microglia/TAM reprogramming). RT reshapes the glioma myeloid ecosystem, and preclinical data indicate a post-RT window in which CSF-1R blockade can mitigate pro-tumor macrophage programs—supporting a timing-aware combination rationale [26]. Early clinical addition of CSF-1R inhibition to chemoradiotherapy is feasible but without clear efficacy in unselected populations [27]. Reprogramming over depletion, biomarker-enriched selection, and careful temporal alignment with RT—plus myeloid-targeted delivery—are favored [29].
JAK–STAT3 (astrocyte–myeloid–tumor axis). STAT3 integrates astrocytic reactivity, immune suppression, and treatment tolerance in GBM. Early-phase experience indicates target engagement and feasibility; activity remains preliminary, arguing for biomarker-informed, RT-timed combinations with microenvironmental and neurocognitive endpoints prespecified [93].
TGF-β signaling (glial scarring, immune exclusion, DDR crosstalk). The TGF-βRI inhibitor galunisertib was combined safely with standard RT/TMZ with pharmacodynamic signals; the rationale for TGF-β/SMAD modulation with RT persists [94].
Chemokine trafficking (CCR2/CCL2). CCR2 antagonism depletes suppressive myeloid cells, unmasks checkpoint efficacy, and prolongs survival in models—supporting triplets with RT + PD-1 blockade in myeloid-inflamed phenotypes, with biomarker selection [6,95].
DDR modulation (ATM). AZD1390, a brain-penetrant ATM inhibitor, shows manageable safety with RT and supportive CNS pharmacokinetics; efficacy signals are still preliminary, and cognitive safety/white-matter integrity warrant prospective monitoring [96].
Lipid/redox homeostasis (TMEM164–FASN–NADPH–ROS). Early mechanistic data implicate TMEM164 as a metabolic gatekeeper of GBM radioresistance via FASN-coupled NADPH and ROS buffering; denifanstat has clinical feasibility in HGA. Candidate strategy: RT-timed FASN inhibition in TMEM164-high tumors, with glia-aware PD readouts (neuroinflammation imaging, serum EV/oxidative markers) and cognitive safety endpoints [72,73].

7.2. Precision Delivery Across BBB/BTB and Glial Compartment

Implantable or MR-guided focused ultrasound (FUS) BBB opening. Repeated SonoCloud-9 activation safely enlarged BBB-opening volumes in recurrent GBM and enabled higher intratumoral chemotherapy exposure; repeated openings with albumin-bound paclitaxel were also feasible [97,98,99,100].
Myeloid-targeted nanocarriers. Hydroxyl-dendrimers that home to activated microglia/TAMs deliver CSF-1R inhibitors or anti-inflammatory payloads selectively within GBM, aligning drug with RT fractions while limiting systemic exposure [29,101].
Nanoradiosensitizers. Next-generation nanoparticle radiosensitizers (high-Z, DNA-repair interference, redox amplification) are advancing toward GBM applications; incorporation into RT-centric regimens will hinge on optimized brain delivery (e.g., via FUS or ligand targeting) [102].
Tumor Treating Fields (TTFields). Beyond being an FDA-approved, guideline-endorsed device therapy that improved progression-free and overall survival when added to maintenance temozolomide in newly diagnosed GBM, emerging preclinical and first-in-human imaging data indicate that TTFields can transiently increase BBB permeability, a feature that might be exploitable to enhance CNS drug delivery; clinical validation of this BBB-modulating effect is ongoing [103,104].

7.3. Biomarkers for Selection, Response Monitoring, and Safety

TSPO as a glia-imaging handle. High TSPO expression marks mesenchymal/immune-rich subpopulations; TSPO-PET may aid detection and provide PD readouts, though cellular specificity and standardization remain in progress [30,105].
MRI radiomics/radiogenomics for immune–glia states. Models now estimate TAM infiltration and immune phenotypes from conventional MRI and link them to survival and (preclinically) immunotherapy benefit [106,107].
EVs as a liquid biopsy. A 2024 consensus reviews highlight EV cargo as accessible markers of heterogeneity and TME crosstalk, with the potential to track glia-directed therapy effects and treatment-related inflammation in real time [65].
Together, these axes support biomarker-first, delivery-enabled trials aligned with RT timing.

8. Future Directions and Clinical Implications

We translate mechanistic insights into practical design principles for trials and daily practice.

8.1. Co-Designing Tumor Control and Neuroprotection

Glia are programmable determinants of both radio/chemo-resistance and radiotoxicity. Strategies should treat radiosensitization and neuroprotection as coupled aims: leverage myeloid and astrocytic reprogramming around RT (e.g., post-RT CSF-1R blockade; STAT3 and TGF-β control), and protect cognition by sparing neurogenic/white matter niches and dampening complement–microglia synapse pruning when feasible. HA-WBRT with memantine already demonstrates cognitive preservation without compromising disease control and can serve as a model across indications [87].

8.2. What to Combine with RT (and When)

Recommended timing relative to radiotherapy and primary readouts are outlined in Table 2.
Table 2. Glia-informed levers, timing, and primary endpoints.
CSF-1R inhibitors. Strong preclinical rationale for post-RT scheduling; early clinical feasibility but limited benefit in unselected populations—favor biomarker-enriched designs [26,27].
STAT3/TGF-β modulators. WP1066 shows target engagement; galunisertib shows safety/PD with RT/TMZ—templates for next-generation modulators [93,94].
DDR-sensitization. AZD1390 is a near-term backbone for RT intensification, with careful cognitive safety monitoring.

8.3. Getting Drugs Where They Matter: Delivery Across BBB/BTB

Focused-ultrasound BBB opening. SonoCloud-9 permits repeated, larger-volume BBB opening in rGBM; coupling to RT fractions could increase exposure of glia-targeted agents in peritumoral brain [97].
Myeloid-targeted carriers. Hydroxyl-dendrimers (e.g., BLZ945 payload) concentrate drug at the myeloid interface and improved survival in orthotopic models—an attractive route to radiosensitizing the niche while limiting systemic exposure [26,29].

8.4. Safety Guardrails for Glia-Targeted Intensification

White-matter and hippocampal dose. Enforce hippocampal sparing where oncologically appropriate; track diffusion-MRI metrics alongside cognition [87].
Complement/microglia biology. Given robust preclinical data that C1q deletion or CR3 modulation prevents irradiation-induced synapse loss and cognitive decline, monitor neuroinflammation (e.g., TSPO-PET) and consider sex-specific analyses [63,81].

8.5. Practical Clinical Implications

Plan with glia in mind. In IDH-wild-type GBM managed with RT/TMZ, consider hippocampal sparing (when feasible) and memantine in scenarios analogous to WBRT practice; in focal RT, minimize dose to hippocampi and major association tracts without compromising coverage [87].
Biomarker-enrich early trials. For CSF-1R/CCR2 ± PD-1 combinations, preferentially enroll TSPO-high or macrophage-radiomics-high patients and randomize post-RT vs. concurrent starts to test timing hypotheses [26].
Use delivery platforms. Where available, couple FUS-BBB to RT cycles to gate agents into peritumoral, glia-rich regions; pursue myeloid-targeted carriers in parallel [26,97].
Measure what you modulate. Align neurocognitive/patient-reported outcomes (PROs) batteries with NRG-CC001; add TSPO-PET and radiomics PD where feasible to link benefit to glia-pathway engagement [87,105,106].
These principles set the stage for glia-informed precision RT. We conclude by integrating the overarching themes.

9. Conclusions

Glial biology provides a unifying lens to reinterpret both treatment resistance and radiotoxicity in GBM. Across tumor and peritumoral brain, microglia/monocyte-derived macrophages, reactive astrocytes, and the oligodendrocyte lineage orchestrate programs that promote stemness, invasion, immune evasion, and DNA-damage tolerance—while analogous glial responses in non-neoplastic tissue underlie synaptic dysfunction, white-matter injury, and cognitive decline after cranial irradiation. Shared, targetable mechanisms recur throughout these contexts: IL-6/JAK–STAT3 and TGF-β signaling, chemokine trafficking (e.g., CCR2/CCL2, CX3CR1/CX3CL1), hypoxia-driven metabolic rewiring, EV-mediated cell–cell communication, and DDR/senescence modules.
This convergence reframes radiosensitization and neuroprotection as coupled design problems. Translationally, three pillars emerge: reprogramming—rather than depleting—myeloid and astrocytic compartments (e.g., CSF-1R, STAT3, TGF-β, CCR2); delivery engineering (focused-ultrasound BBB opening; myeloid-targeted dendrimers; emerging nanoradiosensitizers) to raise intratumoral exposure in glia-rich niches without systemic escalation; biomarker-first frameworks (TSPO-PET, macrophage-oriented MRI radiomics, EV liquid biopsy) to enrich patients and provide PD readouts, while clinical endpoints pair PFS/OS with brain-health metrics (standardized neurocognitive batteries, white-matter integrity, PROs).
Immediate practice already reflects glia-aware mitigation (e.g., hippocampal avoidance with memantine where appropriate), and preclinical signals (e.g., post-RT timing windows for CSF-1R inhibition, FLASH-RT neuroprotection) motivate mechanism-anchored trials. Key open questions include robust patient selection for glia-targeted combinations; optimal temporal sequencing with RT/TMZ; durability and safety of state reprogramming vs. depletion; sex- and age-specific susceptibilities (e.g., complement/CR3 biology); CNS pharmacokinetics and on-target engagement; and standardization of TSPO and radiomics pipelines. Addressing these gaps will enable glia-informed precision radiotherapy that seeks both greater oncologic efficacy and cognitive preservation.

Author Contributions

Conceptualization, F.D. and P.T.; methodology, F.D., G.R. and T.C.; validation, T.C., M.V. and G.M.; formal analysis, F.D.; investigation, F.D., P.T. and G.R.; resources, G.B. and P.P.; data curation, F.D.; writing—original draft preparation, F.D.; writing—review and editing, F.D., P.T., G.R. and G.M.; visualization, F.D.; supervision, P.P., M.A.M. and G.M.; project administration, F.D. All authors have read and agreed to the published version of the manuscript.

Funding

This work was conducted within the author’s academic activity at the School of Radiation Oncology, University of Siena, and received no external funding.

Institutional Review Board Statement

Not applicable. This study did not involve human or animal subjects.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Conflicts of Interest

The authors declare no conflicts of interest.

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