Colorectal cancer remains one of the most formidable challenges in global oncology, and a new review published in Cancer Cell International argues that the key to unlocking better treatment may lie not in the cancer cells’ genes alone, but in their metabolism. The review, authored by Alireza Najafi, Reza Falak, Hossein Khorramdelazad and colleagues at institutions including Iran University of Medical Sciences and Rafsanjan University of Medical Sciences, examines how metabolic reprogramming inside colorectal tumors shapes the immune system’s ability to fight back. Its central message is provocative: the metabolic wiring of a tumor may act as a gatekeeper that determines whether immunotherapy succeeds or fails, and drugs that recalibrate that wiring could transform patient outcomes.
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
Cite Scienmag News
APA MLA Chicago
Nathaniel Bowman. (September 24, 2026). How Tumor Metabolism Decides Whether Colorectal Cancer Immunotherapy Works. Scienmag. https://scienmag.com/how-tumor-metabolism-decides-whether-colorectal-cancer-immunotherapy-works/
Nathaniel Bowman. “How Tumor Metabolism Decides Whether Colorectal Cancer Immunotherapy Works.” Scienmag, 24 September 2026, https://scienmag.com/how-tumor-metabolism-decides-whether-colorectal-cancer-immunotherapy-works/. Accessed 24 September 2026.
Nathaniel Bowman. “How Tumor Metabolism Decides Whether Colorectal Cancer Immunotherapy Works.” Scienmag. September 24, 2026. https://scienmag.com/how-tumor-metabolism-decides-whether-colorectal-cancer-immunotherapy-works/
Copy citation Download RIS
Tags: cancer cell energy pathwaysColorectal cancercolorectal cancer metabolismenergy metabolism and tumor growthFASN inhibitorsIDO-1 inhibitorsImmunotherapyimmunotherapy resistance mechanismskynurenineMDSCsmetabolic drugs for colorectal cancermetabolic gatekeeping in cancer treatmentmetabolic reprogramming in cancermetabolic targeting in oncologyMetabolomicsMetforminTregstumor glycolysis and immune responsetumor immune evasion strategiestumor immune microenvironmenttumor metabolismtumor microenvironmentWarburg effectWarburg effect in colorectal cancer
