Tumor Microenvironment in IDH-Mutated and IDH-Wildtype Gliomas: A Comprehensive Review

Gliomas are the most common primary CNS tumors, with an incidence of ~6 per 100,000 annually. Traditional histology has been complemented and reshaped by molecular diagnostics in the 2021 WHO CNS5 classification, which incorporates markers such as IDH1/2 mutation, 1p/19q codeletion, ATRX status, TERT promoter mutation, EGFR amplification, and chromosome +7/−10. IDH mutation status is a major prognostic determinant: IDH-mutated gliomas generally have better outcomes, further improved with 1p/19q codeletion. Oligodendrogliomas and astrocytomas differ in morphology, genetics, and tumor microenvironment (TME) composition, which likely underlies differences in behavior and outcomes. This review examines the TME in IDH-mutated and IDH-wildtype gliomas, highlighting immune, stromal, and neuronal interactions and therapeutic implications.

IDH-mutated gliomas: These tumors typically show lower overall immune infiltration than IDH-wildtype counterparts. Myeloid cells (microglia and macrophages) dominate the immune infiltrate, with plastic polarization across an M1–M2 spectrum; in IDH-mutant settings, a lower proportion of tumor-associated microglia/macrophages and a tendency toward M1 polarization are noted compared with IDH-wildtype GBM. Quantitatively, myeloid cells comprise ~15–30% of low-grade glioma tissue versus ~10–15% in non-neoplastic brain. Single-cell data indicate that macrophage infiltration (more than microglia) increases with grade. IDH-mutant astrocytoma grade 4 has fewer TAMs than IDH-wildtype GBM. Adaptive immunity is reduced: fewer TILs, reduced PD-L1 expression, and diminished IFN-γ signatures and CD8+ T cells. The oncometabolite 2-HG suppresses T-cell recruitment by lowering CXCL9/10, impairs TCR signaling in CD8+/CD4+ T cells via uptake through dicarboxylate transporters, and contributes to immune quiescence. Immune gene profiling (TCGA) delineates LGG subtypes (Im1–Im3) differing in lymphocyte content, macrophage phenotype, checkpoint expression, genetics, and outcomes; Im1 and Im2 are enriched for IDH1 mutation and lower immune infiltrate. Angiogenesis and metabolism: 2-HG activates EGLN prolyl-hydroxylases, suppressing HIF1α, thereby inhibiting angiogenesis and the glycolytic switch. IDH-wildtype gliomas exhibit more glycolytic, hypoxic, and acidic TMEs. Within IDH-mutant tumors, astrocytomas may acquire glycolytic features more than oligodendrogliomas, aligning with worse outcomes. Neuronal and glial interactions: Data on neuron–tumor interactions in IDH-mutant gliomas are limited; glutamate-mediated hyperexcitability likely contributes to growth and invasion, but most evidence derives from high-grade gliomas. Astrocytoma vs oligodendroglioma TME: In IDH-mutant LGGs, astrocytomas show a predominant macrophage signature, while oligodendrogliomas show a microglia signature. Macrophage signatures (CD163, TGF-β1, F13A1) are associated with higher grade, angiogenesis, and BBB changes; microglia signatures include CX3CR1, P2RY12, P2RY13. Astrocytomas tend to have more immunosuppressive lymphocyte profiles (higher PD-1+ CD8+ T cells, TIM-3+ CD4+ T cells, and Tregs) than oligodendrogliomas. 1p/19q codeletion is associated with lower immune infiltration and checkpoint gene expression (possible contribution of genes on 1p/19q such as TGFB1, JAK1, CSF1). Tumor network biology (e.g., GAP43-driven microtubes) supports invasiveness; 1p/19q codeletion correlates with fewer microtubes and interconnections. Pilocytic astrocytoma (PA): Grade 1 PAs, often MAPK/BRAF-altered (e.g., KIAA1549–BRAF), have distinct microenvironments; GBMs harbor more perivascular CD8+ cells, NKs, and macrophages than PAs, while some PA studies reveal bZIP TFs as positive immune regulators. Comparative data between PAs and IDH-mutants remain sparse. IDH-wildtype gliomas/GBM: GBM displays profound intra/inter-tumoral heterogeneity, glioma stem cells (GSCs), and extensive TME crosstalk via gap junctions, extracellular vesicles, nanotubes/microtubes, paracrine factors, and neuron–tumor synapses. AMPA-type glutamate receptors on glioma cells mediate synaptic currents, promoting invasion. Paracrine mediators (e.g., BDNF, GRP78, neuroligin-3 via ADAM10 cleavage) stimulate PI3K-mTOR signaling and growth. GBM exRNA cargo (miRNAs like miR-10b, tRNA/Y RNA fragments) can influence proliferation, invasion, and transcriptional programs (e.g., E2F1). TAMs constitute ~30–50% of GBM mass; bone marrow-derived macrophages increase with grade and correlate with worse outcomes. BBB disruption plus chemokines/cytokines (CCL2, CCL7, GDNF, CSF-1, GM-CSF, HGF, SDF-1) recruit myeloid cells; neutrophils and mast cells also contribute. Immune escape involves TGFβ2-driven T-cell exhaustion, tumor FasL and PD-L1, and Sox2/Oct4-mediated suppression of Th1 chemokines (CCL5, CXCL9/10/11), promotion of Tregs, and M2-like polarization via IL-6/IL-8. PGE2 is abundant and pro-tumorigenic; COX inhibition shows anti-proliferative/migratory effects in vitro, though clinical benefit remains unproven. GSCs within perivascular niches can differentiate toward endothelial/pericyte lineages and respond to hypoxia with VEGF; astrocytes fuel angiogenesis and may undergo neoplastic transformation; oligodendrocytes may exert inhibitory effects via WNT pathway suppression. Genetic context: Oligodendroglioma (IDH-mut, 1p/19q codeleted) often harbors TERT promoter (≈96%), CIC (≈62%), FUBP1 (≈29%), NOTCH1 (≈31%); astrocytoma (IDH-mut, non-codeleted) frequently exhibits ATRX loss (≈87%), TP53 (≈94%), CDKN2A/2B homozygous deletion (≈10%); high-grade astrocytomas may show PDGFRA amplification and PI3K mutations. IDH-wildtype GBM often shows TERT promoter mutation (≈70%), EGFR amplification (≈40%), and +7/−10 signature; H3-altered diffuse midline gliomas (H3K27-altered) and EZHIP represent distinct IDH-wildtype entities. Clinical outcomes: Among IDH-mutants, oligodendroglioma has median OS ~17 years (grade 2) and ~11 years (grade 3), versus ~8–9 years for IDH-mutant non-codeleted astrocytoma. Non-canonical IDH mutations (e.g., IDH2, non-R132H) may confer longer survival than canonical IDH1 R132H. Differences summary: IDH-wildtype tumors feature higher immune infiltration, macrophage predominance, angiogenesis, glycolytic/hypoxic/acidity traits, extensive neuron/glia/stem interactions; IDH-mutant tumors are more immune-quiescent with 2-HG-mediated T-cell suppression and anti-angiogenic effects, and within IDH-mutants, astrocytomas tend toward more immunosuppressive lymphocyte signatures than oligodendrogliomas. Future perspectives: Targeted therapies (e.g., BRAF/NTRK inhibitors; FGFR inhibitors such as infigratinib, pemigatinib; regorafenib) show promise in subsets. Targeting neuron–glioma synapses (AMPA antagonists like talampanel, perampanel) is under study. Despite impressive results in other cancers, checkpoint inhibitors have not yet improved outcomes in LGG/HGG (e.g., CheckMate548 negative); ongoing trials explore combinations (LAG3, IDO1). PARP inhibitors combinations (e.g., olaparib + pembrolizumab + temozolomide; niraparib) are under investigation. MEK inhibition (selumetinib) has activity in pediatric NF1/BRAF-altered gliomas. In H3-altered IDH-wt gliomas, DRD2/ClpP-targeting agents show early signals. Novel targets include CD161 (KLRB1). Cell therapies such as CAR-T/M (targets: B7-H3, EGFRvIII, HER2, IL13Rα2, GD2) are progressing, with early GD2 CAR-T success in H3K27M gliomas. Vaccines (mutant IDH1 peptide; dendritic cell vaccines like DCVax-L; SurVaxM; DSP-7888) and TME-targeting cytokines (e.g., L19TNF, SDF-1 blockade with olaptesed) are being explored. Gene/cell-based cytokine delivery (e.g., Tie2-monocyte IFN-α delivery; tamferon) and anti-angiogenic combinations (bevacizumab; apatinib) are under clinical evaluation.

• IDH mutation status strongly influences TME and prognosis: IDH-mutant gliomas show lower immune infiltration and an immune-quiescent phenotype compared to IDH-wildtype.
• Myeloid composition and grade: Myeloid cells in LGG constitute ~15–30% of tumor vs ~10–15% in non-neoplastic brain; blood-derived macrophages increase with grade and correlate with worse survival; GBM/TAMs can represent ~30–50% of tumor mass.
• IDH-mutant immune features: Fewer TILs, reduced PD-L1, decreased IFN-γ/CD8 signatures; 2-HG impairs chemokine (CXCL9/10) expression and TCR signaling in T cells, inhibiting effector function; 2-HG stimulates EGLN, suppressing HIF1α and angiogenesis.
• Subtype-specific myeloid signatures: Astrocytomas exhibit macrophage signatures (CD163, TGF-β1, F13A1) linked to angiogenesis/BBB changes; oligodendrogliomas show microglia signatures (CX3CR1, P2RY12/13). Astrocytomas harbor higher PD-1+ CD8+, TIM-3+ CD4+, and Tregs vs oligodendrogliomas; 1p/19q codeletion associates with lower immune infiltration and checkpoint expression.
• Metabolic differences: IDH-wildtype gliomas are more glycolytic, acidic, and hypoxic; IDH-mutants have reduced HIF1α and angiogenesis; within IDH-mutants, astrocytomas may become more glycolytic than oligodendrogliomas.
• Neuron–glioma communication: GBM forms glutamatergic synapses via calcium-permeable AMPA receptors, promoting invasion; neuroligin-3 cleaved by ADAM10 stimulates PI3K–mTOR; exRNAs (e.g., miR-10b) regulate proliferation/invasion.
• Genetics: Oligodendroglioma (IDH-mut, 1p/19q-codeleted) often has TERT promoter (~96%), CIC (~62%), FUBP1 (~29%), NOTCH1 (~31%); Astrocytoma (IDH-mut) frequently shows ATRX loss (~87%), TP53 (~94%), CDKN2A/2B deletion (~10%); GBM (IDH-wt) commonly has TERT promoter (~70%), EGFR amplification (~40%), +7/−10 signature; H3K27 alterations define diffuse midline gliomas.
• Survival: Oligodendroglioma mOS ~17 years (grade 2) and ~11 years (grade 3) versus ~8–9 years for IDH-mutant non-codeleted astrocytoma; non-canonical IDH mutations (e.g., IDH2, non-R132H) correlate with longer survival.
• Therapeutic outlook: Checkpoint inhibitors have not improved outcomes in newly diagnosed GBM with methylated MGMT; promising avenues include AMPA antagonists, PARP inhibitor combinations, MEK inhibition in pediatric LGG, DRD2/ClpP targeting in H3-altered gliomas, CAR-T/M cell therapies (including GD2), dendritic cell and peptide vaccines, cytokine delivery strategies, and anti-angiogenic combinations.

This review synthesizes how molecular classification, particularly IDH status and 1p/19q codeletion, aligns with distinct TME states that likely drive clinical behavior. IDH-mutant gliomas’ immune-quiescent, anti-angiogenic microenvironment contrasts with the inflamed, macrophage-rich, glycolytic, and hypoxic TME of IDH-wildtype GBM, explaining differences in aggressiveness and treatment responses. Within IDH-mutants, astrocytomas’ macrophage-predominant and more immunosuppressive lymphocyte milieu may account for relatively worse outcomes compared to oligodendrogliomas. Detailed mechanisms—such as 2-HG-mediated immune suppression and HIF1α inhibition—provide actionable hypotheses for therapy. The integration of neuronal and glial interactions, especially synaptic signaling and paracrine pathways in GBM, highlights additional TME-dependent vulnerabilities. Collectively, these insights support therapeutic strategies that modulate the TME, including immune interventions, targeting neuron–tumor communication, metabolic reprogramming, and anti-angiogenic and cytokine-based approaches.

Molecular profiling has clarified biologically and clinically meaningful subtypes of gliomas with distinct TMEs. IDH-mutant gliomas generally show reduced immune infiltration and angiogenesis, whereas IDH-wildtype GBM features an immunosuppressive but highly infiltrated, angiogenic, and glycolytic microenvironment with extensive intercellular communication. These differences inform the development of TME-targeting therapies. Early signals of efficacy are emerging for CAR-based cellular therapies, vaccines (including mutant IDH1), and novel combinations (e.g., PARP inhibitors, MEK inhibitors in select populations). Future research should refine TME-driven patient stratification, elucidate neuron–glioma and glia–tumor interactions in IDH-mutants, exploit metabolic–immune crosstalk, and optimize combinatorial regimens to overcome immune evasion.

Most available data derive from high-grade gliomas, particularly IDH-wildtype GBM, with fewer comprehensive studies in IDH-mutant tumors and pilocytic astrocytoma. Neuron–tumor and glial interactions in IDH-mutated gliomas remain insufficiently characterized. Differences in study platforms (bulk vs single-cell) and limited functional validation constrain generalizability. As a narrative review, conclusions synthesize heterogeneous sources without primary experimental methods.