Monocarboxylate transporters (MCTs) are a family of membrane proteins that mediate the transport of monocarboxylates such as lactate, pyruvate, and ketone bodies across the plasma membrane, often coupled with H⁺ ions. These transporters are essential for maintaining intracellular and extracellular pH homeostasis and supporting metabolic adaptation, particularly under hypoxic and glycolytic conditions common in malignant tumors.

🔍 MCTs in Glioma Pathobiology

🧬 Key Isoforms: MCT1 (SLC16A1): High affinity for lactate, expressed in both oxidative and glycolytic cells.

MCT4 (SLC16A3): Low affinity but high capacity, induced by hypoxia-inducible factor 1 (HIF-1α) and upregulated in highly glycolytic, hypoxic tumors.

MCT2 (SLC16A7): Highest affinity for lactate, recently recognized for its nuanced regulation in astrocytes and glioma cells in response to pH, hypoxia, glucose, and lactate, as shown by Caruso et al. ¹⁾.

🧪 Molecular Functions in GBM: Glioblastoma (GBM), the most aggressive primary brain tumor, exhibits a hallmark aerobic glycolytic phenotype (Warburg effect), leading to excessive lactate production. MCT1 and MCT4 mediate lactate efflux to prevent “self-poisoning,” facilitating:

Tumor cell survival under metabolic stress

Invasion of surrounding tissue

Immune evasion via acidic microenvironment

🏥 Relevance in Neurosurgical Practice 1. Tumor Aggressiveness & Surgical Planning High MCT1/4 expression correlates with aggressive tumor biology in GBM ²⁾

Their presence may mark invasive margins or hypoxic cores, which are difficult to resect and more likely to recur. Future intraoperative imaging (e.g., hyperpolarized MRI or pH-sensitive probes) may enable visualization of metabolically active MCT-rich zones to optimize resection margins.

2. Pathological Diagnosis and Immunohistochemistry MCT1/4 immunoreactivity can aid in distinguishing IDH-wildtype GBM from lower-grade gliomas when molecular data is incomplete. Pathologists and neurosurgeons may use MCT staining to infer tumor grade, prognosis, and potential therapeutic vulnerability.

3. Adjunctive Therapies Post-Resection Targeting MCTs offers a metabolism-based adjuvant approach.

Syrosingopine, a dual MCT1/4 inhibitor with CNS penetration, demonstrates apoptotic and anti-invasive effects in glioma cell lines and is a candidate for clinical repurposing.

Combined therapies (e.g., with metformin) may synergize to exhaust tumor metabolic plasticity.

4. Neurosurgical Research and Innovation MCTs are a valuable focus in translational neuro-oncology:

Biopsy targeting, tumor banking, and delivery of MCT inhibitors (e.g., via convection-enhanced delivery) are emerging research avenues.

Understanding the pH-lactate-hypoxia interplay via MCT regulation (as described by Caruso et al.) may lead to new molecular imaging markers or pH-responsive delivery systems.

No MCT-targeting therapy is yet approved for clinical neurosurgical use.

Expression heterogeneity within tumors and across patients complicates therapeutic targeting.

Isoform-specific inhibitors with safe CNS profiles are needed.

Non-invasive radiological detection of MCT activity is still under development.

Monocarboxylate transporters—particularly MCT1 and MCT4—are more than molecular curiosities; they are critical markers and mediators of glioma aggressiveness. Their expression informs diagnosis, surgical planning, and offers a metabolic Achilles’ heel that could be exploited through adjuvant therapy. As glioma therapy moves toward precision medicine, MCTs represent a bridge between metabolic biology and neurosurgical practice.