NMDA receptors belong to the ionotropic glutamate receptor family, a class of proteins best known for mediating excitatory synaptic transmission in the brain. When glutamate and a co-agonist bind, the channel pore opens and permits an influx of calcium and sodium ions into the cell. In neurons, this calcium entry triggers cascades that strengthen or weaken synapses. The review’s central premise is that an analogous logic operates in the immune system: tumor tissues are rich in glutamate and related excitatory amino acids, and myeloid cells patrolling that environment express NMDA receptors capable of translating this extracellular metabolic signal into intracellular calcium flux. The result is a signaling axis that couples the metabolic state of the tumor to the functional identity of its immune infiltrate.

The downstream consequences of this calcium signaling are strikingly specific. According to the review, NMDA receptor activity on myeloid cells promotes M2 macrophage polarization, the alternative activation state characterized by expression of markers such as CD163, CD206, and the mannose receptor Mrc1, along with production of interleukin-10 rather than the inflammatory interleukin-12. M2-polarized tumor-associated macrophages suppress cytotoxic T cell activity, remodel the extracellular matrix, and secrete growth factors that support angiogenesis and metastatic spread. In parallel, NMDA-driven signaling enhances the suppressive capacity of myeloid-derived suppressor cells, or MDSCs, a heterogeneous population that inhibits T cell responses through production of reactive oxygen and nitrogen species, arginase-1-mediated depletion of L-arginine, and indoleamine 2,3-dioxygenase-driven catabolism of tryptophan.

Technically, the calcium influx through NMDA receptors engages several well-characterized intracellular pathways. The review describes activation of the MAPK and ERK cascades, the cAMP response element-binding protein CREB, and the signal transducer and activator of transcription STAT3, each of which has established roles in driving pro-tumor myeloid differentiation. Transcription factors including PPARγ and KLF4, hallmarks of M2 programming, are also implicated. Beyond transcriptional changes, calcium-dependent signaling reshapes myeloid metabolism itself, shifting cells toward fatty acid oxidation and oxidative phosphorylation, the bioenergetic profile typical of immunosuppressive M2 macrophages, and away from the glycolytic, inflammatory program of M1 cells. The kynurenine pathway of tryptophan degradation, with enzymes such as IDO, TDO, KMO, and 3-hydroxyanthranilate 3,4-dioxygenase, emerges as a metabolic bridge connecting glutamate signaling to the generation of immunosuppressive metabolites like quinolinic acid, itself an endogenous NMDA receptor agonist.

This last point hints at a self-reinforcing loop that the authors highlight as particularly consequential for tumor biology. Tumor cells and myeloid cells release glutamate into the extracellular space, and excitatory amino acid transporters and glutamate-metabolizing enzymes such as glutamate carboxypeptidase II, which cleaves N-acetylaspartylglutamate, modulate local ligand availability. Activated myeloid cells then produce kynurenine pathway metabolites, some of which further stimulate NMDA receptors, sustaining calcium signaling and consolidating the suppressive phenotype. In this model, the tumor microenvironment becomes an ecosystem in which ion channel activity, amino acid metabolism, and immune cell differentiation feed one another, progressively locking the infiltrate into a state that tolerates rather than attacks the malignancy.

The review also situates NMDA signaling within the broader landscape of ion channel immunometabolism. Various classes of ion channels, including calcium, sodium, and potassium channels, function as sensors of metabolic cues, converting changes in the extracellular ionic and nutrient milieu into altered immune cell behavior. What distinguishes NMDA receptors is their ligand-gated nature and their exquisite sensitivity to the amino acid composition of the microenvironment, which makes them uniquely positioned to integrate tumor-derived metabolic signals. The authors frame this as an extension of immunometabolism research, arguing that ion influx is not merely a downstream consequence of immune activation but an upstream determinant of cell fate, shaping whether a myeloid cell becomes an antigen-presenting ally of antitumor immunity or a suppressive accomplice of the tumor.

Perhaps the most clinically provocative section of the review concerns immunotherapy. Immune checkpoint inhibitors targeting PD-1 and PD-L1 have transformed treatment for melanoma, lung cancer, and other malignancies, yet many patients either do not respond or eventually relapse, frequently because suppressive myeloid cells dominate the tumor microenvironment. The review compiles recent studies indicating that combining NMDA receptor antagonists, or antagonists of related ionotropic glutamate receptors such as AMPA and kainate receptors, with anti-PD-1 or anti-PD-L1 therapy enhances immunotherapy efficacy in preclinical settings. By blocking calcium-driven myeloid reprogramming, these antagonists appear to soften the immunosuppressive barrier that otherwise blunts checkpoint blockade, allowing cytotoxic CD8-positive T cells, natural killer cells, and antibody-dependent cellular cytotoxicity mechanisms to operate more effectively.

The therapeutic logic extends to other facets of myeloid biology described in the review. Suppressive myeloid cells contribute to resistance through neutrophil extracellular traps, elastase and myeloperoxidase release, expression of checkpoint molecules such as Lag-3 and TIM-3, and secretion of vascular endothelial growth factor and transforming growth factor beta. NMDA receptor signaling intersects with hypoxia-inducible factor 1 alpha-driven adaptation to the hypoxic tumor core and with Notch pathway regulation, adding further layers to the network that ion channel blockade could perturb. The authors also note connections to epithelial-to-mesenchymal transition and matrix remodeling via fibronectin, suggesting that myeloid NMDA signaling may influence not only immune evasion but also invasion and metastatic behavior.

Several caveats temper the enthusiasm. The evidence base is drawn largely from preclinical models and correlative human studies, and the precise expression patterns of NMDA receptor subunits on distinct myeloid subsets in human tumors remain incompletely mapped. Systemic NMDA receptor blockade carries well-known neurological risks, given the receptors’ essential roles in synaptic plasticity, so translating this biology into the clinic will require careful attention to pharmacology, dosing, and possibly tumor-selective delivery strategies. The review, which was funded by Warsaw University of Technology through its Excellence Initiative: Research University program and published open access, is explicit that ion channel signaling represents an attractive target whose therapeutic window must still be defined.

Even so, the synthesis marks a conceptual shift worth attention. For decades, cancer immunology has focused on ligands, cytokines, and checkpoint proteins as the currency of immune regulation. This review argues that ions, and the channels that admit them, deserve equal billing. If calcium entry through NMDA receptors genuinely determines whether macrophages and MDSCs defend the host or defend the tumor, then the glutamate-rich, metabolically warped interior of a cancer is not just background noise but an active instructional signal, one that can be intercepted. As combination strategies pairing ion channel antagonists with checkpoint inhibitors move toward validation, the humble synaptic receptor may find a second career at the front lines of oncology, turning the tumor’s own metabolic language against it.

Subject of Research: The role of NMDA ion channels in calcium-dependent myeloid cell reprogramming within the tumor microenvironment and its impact on cancer immunotherapy

Article Title: N-methyl-D-aspartate (NMDA) ion channels drive calcium-dependent myeloid cell reprogramming to shape cancer immunity and immunotherapy

Article References: Zaremba, D. D., Czarnecka, A. M., & Wińska, P. (2026). N-methyl-D-aspartate (NMDA) ion channels drive calcium-dependent myeloid cell reprogramming to shape cancer immunity and immunotherapy. Cancer Immunology, Immunotherapy. https://doi.org/10.1007/s00262-026-04483-z

Image Credits: AI Generated

DOI: 10.1007/s00262-026-04483-z

Keywords: NMDA receptors, ion channels, calcium signaling, myeloid cells, M2 macrophages, MDSCs, tumor microenvironment, immunometabolism, immune evasion, anti-PD-1/PD-L1, cancer immunotherapy, glutamate signaling

At the heart of the review is the concept of metabolic reprogramming, the process by which cancer cells fundamentally alter how they generate energy and build the molecular components needed for relentless growth. The most famous example is the Warburg effect, a phenomenon first described nearly a century ago in which cancer cells preferentially burn glucose through glycolysis even in the presence of abundant oxygen, a strategy that would seem inefficient but turns out to support rapid proliferation. By enhancing glycolytic flux, colorectal cancer cells rapidly consume glucose from their surroundings while flooding the tumor microenvironment with lactate, a metabolic byproduct that acidifies the tissue and undermines the function of immune cells that would otherwise attack the tumor.

The consequences of this metabolic competition extend far beyond glucose. The review details how alterations in lipid metabolism allow tumor cells to synthesize the fatty acids required for building new membranes as they divide, while amino acid metabolism provides the nitrogen and carbon skeletons for producing proteins and nucleotides. One particularly important amino acid is glutamine, which fuels multiple biosynthetic pathways, and another is tryptophan, whose breakdown has emerged as a critical immune escape mechanism. Together, these metabolic shifts do not merely feed the tumor; they actively sculpt the surrounding environment into one that suppresses immune activity and fosters therapeutic resistance.

The tumor microenvironment in colorectal cancer, as the review describes it, becomes a battlefield defined by metabolites. Immune cells that infiltrate the tumor find themselves starved of the glucose and amino acids they need to sustain their anti-tumor activity, while simultaneously being exposed to an accumulating pool of immunosuppressive metabolites. Among the most notorious of these is kynurenine, a product of tryptophan catabolism that directly inhibits T cell activity. The metabolic conditions within the tumor also promote the expansion of regulatory T cells, or Tregs, a specialized immune cell type that normally restrains excessive immune responses but which tumors co-opt to shield themselves from attack. Myeloid-derived suppressor cells, or MDSCs, another population of immunosuppressive cells, are likewise favored by the altered metabolic landscape, compounding the barrier to effective anti-tumor immunity.

This is where the concept of metabolic modulators as gatekeepers becomes central to the review’s argument. Immune checkpoint inhibitors, the class of immunotherapy drugs that have revolutionized treatment of several cancers, depend on the presence of functional, energized T cells to work. In colorectal cancer, however, the metabolically hostile tumor microenvironment often renders T cells exhausted and dysfunctional, meaning that releasing the brakes on the immune system achieves little when the engine itself has run out of fuel. The review emphasizes that targeting the metabolic pathways responsible for this dysfunction, including glycolysis, oxidative phosphorylation, and amino acid metabolism, can simultaneously disrupt tumor proliferation and restore the anti-tumor immune responses that immunotherapy requires.

Several classes of metabolic drugs have already shown promise in preclinical and clinical contexts, according to the authors. Fatty acid synthase inhibitors, known as FASN inhibitors, aim to cut off the tumor’s capacity to manufacture its own lipids, a vulnerability that many rapidly dividing cancers cannot easily bypass. Metformin, the widely used and inexpensive diabetes drug, has attracted intense oncology interest because of its effects on cellular energy sensing pathways, and the review highlights its potential to improve immunotherapy responses in colorectal cancer. Inhibitors of indoleamine 2,3-dioxygenase 1, or IDO-1, target the enzyme responsible for degrading tryptophan into kynurenine, thereby addressing one of the most direct mechanisms by which tumors starve and suppress T cells. By combining these metabolic interventions with checkpoint blockade, the authors suggest, clinicians may be able to overcome the resistance mechanisms that currently limit immunotherapy in many colorectal cancer patients.

The technical logic behind these combinations is grounded in the interdependence of glucose, lipid, and amino acid metabolism. Blocking a single pathway rarely defeats a tumor outright, because cancer cells are metabolically flexible and can compensate through alternative routes. However, metabolic stress imposed on tumor cells can tipping the balance of the microenvironment: less lactate means less acidity, more available glucose means better-fueled cytotoxic T cells, and preserved tryptophan levels mean less kynurenine-mediated suppression. When these favorable metabolic shifts are layered onto immunotherapy, the checkpoint inhibitors encounter a population of T cells that is genuinely capable of proliferating and killing tumor cells, rather than a depleted and exhausted contingent. The review frames this metabolic recalibration as a strategy that could extend the benefits of immunotherapy to patients whose tumors are currently classified as unresponsive.

Beyond treatment, the review underscores the growing role of metabolomic and multi-omics profiling in personalized colorectal cancer care. These techniques allow researchers to measure hundreds of metabolites and metabolic gene signatures in a patient’s tumor simultaneously, generating a metabolic fingerprint that could predict how an individual will respond to immunotherapy before treatment begins. Such biomarkers would represent a significant advance over current approaches, in which immunotherapy is often administered empirically and its effectiveness assessed only after weeks of treatment. By identifying which metabolic pathways dominate in a given patient’s tumor microenvironment, clinicians could in principle select the most appropriate metabolic modulator to pair with immunotherapy, moving the field closer to truly personalized therapeutic regimens.

The authors, whose work was supported by Rafsanjan University of Medical Sciences, are careful to position their analysis as a synthesis of the current evidence landscape rather than a report of a single new experiment. As a review, the article draws together findings from preclinical models and clinical studies to build a coherent framework connecting tumor metabolism, immune evasion, and immunotherapy response. The framework carries important caveats that the field itself continues to grapple with: systemically delivered metabolic drugs affect both tumor cells and immune cells, sometimes with opposing consequences, and patients’ overall metabolic state, influenced by diet, obesity, diabetes, and the gut microbiome, adds further layers of complexity that laboratory models struggle to fully replicate.

Nevertheless, the review’s core thesis offers a compelling reframing of an old problem. Colorectal cancer has long been considered relatively resistant to immunotherapy compared with melanoma and lung cancer, and much of the research effort has focused on genetic and immune-cell-based explanations. By spotlighting metabolism as the decisive variable, Najafi, Falak, Khorramdelazad and their colleagues point toward a therapeutic frontier in which the tumor’s own fuel supply becomes its greatest vulnerability. If ongoing and future clinical studies validate the promise of metabolic modulators, the gatekeeper metaphor may prove apt in the most literal sense: controlling what crosses the metabolic gates of the tumor microenvironment could determine who benefits from the immunotherapy revolution and who is left behind.

Subject of Research: Metabolic reprogramming and metabolic modulators as determinants of immunotherapy response in colorectal cancer

Article Title: Metabolic modulators as gatekeepers of immunotherapy response in colorectal cancer

Article References: Najafi, A., Rahimi, A., Baghernejadian, Z., Hazrati, A., Malekpour, K., Samimi, L. N., Falak, R., & Khorramdelazad, H. (2026). Metabolic modulators as gatekeepers of immunotherapy response in colorectal cancer. Cancer Cell International. https://doi.org/10.1186/s12935-026-04471-4

Image Credits: AI Generated

DOI: 10.1186/s12935-026-04471-4

Keywords: colorectal cancer, immunotherapy, tumor metabolism, Warburg effect, kynurenine, IDO-1 inhibitors, metformin, FASN inhibitors, tumor microenvironment, Tregs, MDSCs, metabolomics