Cancer Cells Run on a Metabolic Hybrid Engine, and Surgeons May Soon Map It

Mitochondria, the organelles long caricatured as little more than cellular power plants, are staging one of the most compelling comebacks in modern cancer biology. A comprehensive review published in Experimental Biology and Medicine argues that mitochondrial metabolism is not a passive byproduct of tumor growth but an active determinant of it, supplying the building blocks for macromolecule synthesis and the adaptive programs that let cancer cells survive hostile environments. Drawing on studies in humans and mice, the authors, led by Debdeep Chattopadhyay, Ramya Lakshmi Rajendran, Nida Mubin and senior investigators Prakash Gangadaran and Byeong-Cheol Ahn, synthesize evidence spanning mitochondrial DNA mutations, redox biology, apoptotic priming and immune regulation, and they connect these mechanisms to a question that has rarely been asked so directly: how should metabolic targeting be woven into surgical cancer care?

The review’s central provocation is that the famous Warburg effect, the observation that cancer cells preferentially ferment glucose into lactate even in the presence of oxygen, is an incomplete map of tumor metabolism. Tumors, the authors emphasize, are far more metabolically diverse than the Warburg model suggests. Cancer cells possess a dual capacity: many can oxidize glucose through fully functional mitochondria via oxidative phosphorylation, or OXPHOS, while simultaneously running glycolysis. Strikingly, some cells occupy hybrid states in which both pathways operate concurrently, feeding energy production and biomass synthesis at the same time. Systems-level modeling and gene-signature approaches, such as quantifying downstream targets of AMPK and HIF-1, now provide tools to measure where a given tumor sits on this glycolytic-to-oxidative spectrum.

This plasticity is not a biochemical curiosity; it is clinically consequential. Hybrid glycolysis/OXPHOS phenotypes are specifically associated with metastasis and therapy resistance, and coexisting cell populations within a single tumor can reverse their energetic control, switching between sugar fermentation and oxygen-based respiration in response to environmental cues or drug pressure. The mechanistic wiring involves oncogenic and stress-responsive pathways converging on shared glycolytic effectors. The enzymes HK2, PKM2 and LDHA are targets of both c-Myc and hypoxia-inducible factors, while PI3K–AKT–mTOR signaling drives nutrient uptake and anabolic growth and AMPK guards the energy balance. Because these circuits interact, a single tumor can harbor genuinely different metabolic states in its oxygen-starved core versus its well-perfused margin, complicating any therapy that blocks just one pathway.

Within that heterogeneity, some tumors are strikingly dependent on mitochondrial respiration. Preclinical development of complex I inhibitors has flagged acute myeloid leukemia, subsets of lymphoma, glioblastoma, triple-negative breast cancer, melanoma and pancreatic ductal adenocarcinoma as OXPHOS-reliant contexts. Melanoma is the canonical example: PGC-1α-driven mitochondrial oxidative metabolism is described as essential for the growth and survival of a defined subset of human melanomas, a biologically grounded metabolic subtype that could, in principle, be identified in surgical specimens and used to stratify patients. The review argues that this phenotype-aware view, rather than an assumption of uniform glycolytic dependence, should anchor future translational studies.

Mitochondrial DNA adds another layer of vulnerability and opportunity. Unlike nuclear DNA, mtDNA is not protected by histones, making it exceptionally susceptible to oxidative damage generated inside the mitochondrial matrix. Mutations in genes encoding respiratory chain complexes I, III and IV appear across cancers and can reshape metabolism in ways that enhance tumorigenesis and adaptation. Crucially, the functional impact of any mutation depends on heteroplasmy, the proportion of mutant to wild-type genomes in each cell, so a mutation list alone cannot predict metabolic behavior. Yet mtDNA features may soon guide treatment: in a 2024 study of 308 patients with mismatch repair–deficient colorectal cancer, higher tumor mitochondrial DNA copy number correlated with better disease-free and overall survival, and those patients appeared to derive greater benefit from adjuvant chemotherapy. Because mtDNA copy number can be measured in resected tissue, it is an attractive perioperative biomarker, though the authors stress it still requires prospective validation.

The therapeutic record is humbling, and the review does not soften it. Metformin, the widely repurposed respiratory inhibitor, failed in the phase III MA.32 trial: adding it to standard therapy did not improve invasive disease–free survival in unselected early breast cancer, and it produced more grade 3 nonhematological toxicities and poorer adherence. Intriguingly, metformin did measurably lower CA 15-3 and estradiol levels, proof that biomarker modulation does not guarantee survival benefit without proper patient selection. More dramatic still is the story of IACS-010759, a potent, selective complex I inhibitor that entered phase I trials in relapsed or refractory acute myeloid leukemia and advanced solid tumors. Dose-limiting lactate elevation and neurotoxicity produced a narrow therapeutic index, no recommended phase 2 dose could be established, target inhibition was modest, and the trials were discontinued. Meanwhile, devimistat, a lipoate analog targeting two TCA cycle enzyme complexes, failed to improve survival when added to modified FOLFIRINOX in metastatic pancreatic cancer in the phase III AVENGER 500 trial.

Apoptosis targeting tells a sharper two-sided tale. Venetoclax, a BH3 mimetic that selectively neutralizes the anti-apoptotic protein BCL-2, transformed outcomes in acute myeloid leukemia: in the phase 3 VIALE-A trial, azacitidine plus venetoclax extended overall survival in previously untreated patients ineligible for intensive chemotherapy. That is clinical proof of principle that manipulating mitochondrial apoptotic priming can work. But translation to solid tumors has faltered, exemplified by the randomized phase II VERONICA trial, in which venetoclax plus fulvestrant did not significantly improve clinical benefit rate or progression-free survival in ER-positive, HER2-negative metastatic breast cancer. Broader BCL-2 family inhibition carries its own liabilities, with navitoclax’s thrombocytopenia a recurring dose-limiting concern, and venetoclax-associated events such as tumor lysis syndrome would complicate perioperative timing.

What elevates this review beyond a standard mechanism summary is its surgical framing. The authors propose that resected tumors become maps rather than samples: mass spectrometry imaging could chart metabolites across anatomically defined regions such as tumor core, invasive margin, hypoxic zones and adjacent healthy tissue, while matched single-cell sequencing and spatial transcriptomics would link those metabolic landscapes to specific malignant, stromal and immune cell populations. Integrating such data with histopathology, treatment exposure and outcomes could identify glycolytic, OXPHOS-dependent and metabolically plastic subpopulations associated with response, resistance or recurrence, and reveal cells that switch fuel sources after therapy and thereby seed relapse. Timing matters too: because postoperative recovery demands a metabolic shift from catabolism to repair, broad mitochondrial inhibition around surgery could interfere with healing and would need careful scheduling alongside nutritional status and wound recovery.

The immune dimension adds a final twist. Mitochondrial fitness is essential for antitumor T cells: OXPHOS and complex III-derived reactive oxygen species support NFAT signaling, IL-2 production and antigen-specific expansion, while the tumor microenvironment’s hypoxia and nutrient deprivation suppress PGC-1α-driven mitochondrial biogenesis in CD8-positive T cells, pushing them toward terminal exhaustion. Restoring mitochondrial fitness can reinvigorate these cells, so any therapy intended to cripple tumor mitochondria must spare those of infiltrating lymphocytes. Meanwhile, mtDNA released into the cytosol or extracellular space activates cGAS–STING, TLR9 and inflammasome pathways, linking mitochondrial injury to innate immunity, and mitochondria-targeted sensitizers that release damage-associated molecular patterns are being explored for immunogenic cell death. Early clinical signals include a phase I dose-escalation trial of an engineered mitochondrial vaccine in advanced solid tumors, registered with objective response rate endpoints but no outcomes yet reported, and preclinical work showing that the mitochondria-targeted antioxidant MitoQ radiosensitizes MDA-MB-231 but not MCF7 breast tumors, prevented recurrence and metastasis in mouse models at nanomolar concentrations that spared nonmalignant cells, and has a defined response signature for bulk biopsies.

The synthesis that emerges is deliberately unsentimental: mitochondrial vulnerabilities are a context-dependent opportunity, not a universal off switch. The authors call for metabolic phenotype classification, biomarker-guided patient selection and rational combinations, with pharmacodynamic readouts such as the rise in mitochondrial-to-genomic DNA ratio observed during complex I inhibition, and continued development of increasingly precise mitochondrial genome editors whose off-target edits have been reduced by more than 99 percent in preclinical systems. The near-term payoff is unlikely to be a single metabolic drug; it will more likely be a workflow in which a surgical specimen is spatially profiled, a tumor’s hybrid metabolic state is quantified, and a mitochondria-directed intervention is timed and combined accordingly. If that vision holds, the organelle once dismissed as an evolutionary passenger in cancer may become the anatomical and therapeutic reference point of multimodal oncology.

Subject of Research: Mitochondrial metabolic plasticity, hybrid glycolysis/OXPHOS states, and biomarker-guided therapeutic targeting in surgical oncology

Article Title: Mitochondrial metabolic plasticity in cancer: hybrid bioenergetic states and translational targeting in surgical oncology

Article References: Mitochondrial metabolic plasticity in cancer: hybrid bioenergetic states and translational targeting in surgical oncology. (n.d.). https://doi.org/10.3389/ebm.2026.11244

Image Credits: AI Generated

DOI: 10.3389/ebm.2026.11244

Keywords: mitochondria, cancer metabolism, OXPHOS, glycolysis, Warburg effect, metabolic plasticity, mitochondrial DNA, surgical oncology, OXPHOS inhibitors, venetoclax, tumor microenvironment, biomarkers