---
title: "Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: immune remodelling and immunoth"
id: "frontiers-in-immunology-17-redox-driven-mitochondrial-dna-stress-in-hepatocellular-carcinoma-innate-immune"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-17-redox-driven-mitochondrial-dna-stress-in-hepatocellular-carcinoma-innate-immune"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1903643"
published_at: "2026-09-04T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: immune remodelling and immunoth
## Provenance & Clinical Metadata
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- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1903643)
- **Published At:** 2026-09-04T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- The source record identifies a REVIEW article titled "Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications" published in Frontiers in Immunology. - The visible source content is page navigation and journal metadata; the main article body and review content are not present in the provided source text. - The title highlights key concepts: **hepatocellular carcinoma**, **mitochondrial DNA stress**, **redox-driven** processes, **innate immune remodelling**, **tumour immune escape**, and **immunotherapy implications**. - No study data, methods, results, author list, conclusions, or specific mechanistic or clinical details were reported in the supplied source content. - Because the article text was not included, specifics such as pathways, experimental systems, biomarkers, therapeutic strategies, or recommendations were not available from this source. - The supplied material contains only Frontiers in Immunology site navigation, sections listings, and journal information; it does not provide the review's substantive content or findings. - For clinicians or researchers seeking the full review, the provided source URL and journal landing pages are the only pointers given; the full text must be accessed at the publisher site to obtain the review details. - Any mechanistic, preclinical, or clinical implications referenced by the title cannot be summarized from the present source and therefore were not reported here.
## Clinical Analysis & Structured Key Points
Frontiers | Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications REVIEW article Front. Immunol. , 04 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1903643 Published in Frontiers in Immunology Cancer Immunity and Immunotherapy 7 impact factor 11.3 citescore Editor & Reviewers Edited by J B Jorge B. Aquino Reviewed by G M Gabriele Missale S S Sebastian Schloer Outline Figures and Tables Figure 1 View in article Figure 2 View in article Table 1 Evidence tiers and interpretive limits of the redox–mtDNA–innate immune framework in hepatocellular carcinoma. View in article Table 2 Minimum evidence and key limitations for translational development of redox–mtDNA-directed strategies in hepatocellular carcinoma. View in article REVIEW article Front. Immunol. , 04 September 2026 Sec. Cancer Immunity and Immunotherapy Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1903643 Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications Z C Ze Chang 1 G L Guannan Liu 2 J Z Jinshan Zhang 3 H L Hailin Lei 1 H Q Haiyan Quan 1 * Y P Ying Piao 2 * 1. Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, China 2. Emergency Department, The Affiliated Hospital of Yanbian University, Yanji, China 3. Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China See more Article metrics View details Abstract Hepatocellular carcinoma (HCC) develops in a chronically injured liver where metabolic adaptation, oxidative stress, innate immune signalling, and immune tolerance are already intertwined. Mitochondria connect these processes: they sustain tumour-cell fitness, yet damaged organelles expose mitochondrial DNA (mtDNA) as an intracellular and intercellular danger signal. Persistent reactive oxygen species, altered mitochondrial dynamics, nucleoid instability, and incomplete mitophagy–lysosomal clearance can oxidise, fragment, and displace mtDNA. The resulting material may remain in the cytosol, circulate freely or in protein-associated complexes, or be transferred within extracellular vesicles. These forms are not immunologically equivalent. Cytosolic mtDNA favours cGAS–STING access; endocytosed material can engage endolysosomal TLR9; and oxidised mtDNA can cooperate with mitochondrial reactive oxygen species, ATP, cardiolipin, and ionic perturbation in NLRP3 inflammasome-associated signalling. Redox remodelling also alters interferon responsiveness, inflammasome competence, and myeloid-cell metabolism, allowing recipient cells to assign different meanings to a similar mitochondrial signal. We integrate these mechanisms into an acute immune activation–chronic immune adaptation continuum. Transient, spatially restricted, and efficiently cleared danger can support antigen presentation and effector recruitment, whereas recurrent or poorly cleared signalling can become embedded in suppressive myeloid remodelling, lymphocyte dysfunction, and spatial immune escape. Direct HCC studies support treatment-induced mtDNA–STING activation, hypoxic extracellular-vesicle-mediated mtDNA transfer, macrophage TLR9 signalling, and TFAM–mtDNA–NLRP3 coupling. The transition between immune states remains a testable synthesis, not an established linear pathway. Therapeutic intervention should be matched to signal form, recipient-cell competence, timing, spatial context, and hepatic reserve; pathway activation alone is an inadequate guide. 1 Introduction Hepatocellular carcinoma (HCC), which accounts for most primary liver cancers, remains a major cause of cancer-related mortality despite advances in surveillance, locoregional therapy, molecularly targeted treatment, and immunotherapy ( 1 , 2 ). Its aetiological distribution is changing: chronic hepatitis B virus (HBV) infection remains dominant in many regions, hepatitis C virus (HCV) infection and alcohol-related disease continue to contribute substantially, and metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH) ( 3 ) account for a growing proportion of cases ( 4 , 5 ). These conditions differ biologically, but all place malignant transformation within a liver already shaped by repeated injury, fibrosis, vascular remodelling, and physiological immune tolerance ( 1 , 6 , 7 ). Systemic immunotherapy has shown that antitumour immunity can be restored in a subset of patients. Atezolizumab plus bevacizumab and tremelimumab plus durvalumab improved outcomes in advanced HCC ( 8 , 9 ). By contrast, LEAP-002 did not meet its prespecified overall- and progression-free-survival thresholds ( 10 ), illustrating that adding checkpoint blockade to an active targeted backbone does not uniformly overcome resistance. Clinical benefit remains heterogeneous. The presence of an immune target does not identify the limiting immune defect. Tumours differ in aetiology, vascularisation, metabolic state, myeloid composition, antigen-presenting-cell competence, and the extent to which chronic liver disease has already remodelled innate and adaptive immunity ( 6 , 7 ). A mechanistic account of treatment response must explain how tumour-cell injury is communicated to surrounding cells and why an inflammatory signal produces coordinated tumour control in one setting but chronic, tumour-supporting adaptation in another. Mitochondria provide a plausible interface between tumour adaptation and immune communication. HCC cells reconfigure glucose, lipid, and amino-acid metabolism to survive hypoxia, nutrient limitation, and therapeutic pressure while retaining mitochondrial functions required for ATP production, biosynthesis, and redox buffering ( 11 – 14 ). This compensation can preserve cell viability without fully restoring mitochondrial membranes, respiratory function, nucleoid organisation, or quality control. A normally sequestered mitochondrial genome can consequently become oxidised, fragmented, displaced into the cytosol, or released between cells, converting metabolic stress into an intracellular and intercellular danger signal ( 15 , 16 ). The immune meaning of mtDNA is determined both before and after receptor engagement. Cytosolic mtDNA can activate cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) ( 15 , 16 ); endocytosed mtDNA can reach Toll-like receptor 9 (TLR9) ( 16 , 17 ); and oxidised mtDNA can contribute to NLRP3 inflammasome-associated signalling ( 15 , 16 ). Signal form, packaging, persistence, clearance, recipient-cell identity, and the surrounding metabolic state then determine whether these routes support type I interferon production and antigen presentation ( 18 , 19 ) or instead sustain nuclear factor kappa B (NF-κB)-skewed inflammation ( 20 , 21 ), programmed death-ligand 1 (PD-L1) expression ( 22 ), suppressive macrophage adaptation ( 20 , 21 , 23 ), and tissue injury ( 23 ). Redox remodelling is therefore not only an upstream source of mtDNA damage; it also changes the competence of tumour and immune cells to interpret mitochondrial material ( 24 , 25 ). We organise these divergent outcomes along an acute immune activation–chronic immune adaptation continuum. This is not a simple distinction between short and long exposure. A single intense treatment-associated release, repeated transient leakage, persistent low-level exposure, or inefficient clearance can follow different trajectories according to mtDNA oxidation and packaging, the route of delivery, the recipient compartment, and the pre-existing liver environment. Productive signalling requires temporal coordination between danger release, antigen availability, competent sensing, antigen presentation, effector recruitment, and resolution. When mitochondrial danger is recurrent or unresolved, it can instead be incorporated into suppressive myeloid differentiation, lymphocyte dysfunction, vascular and stromal restriction, and spatial immune escape. mtDNA is the principal organising signal in this Review, but it is released within a broader mitochondrial danger environment. Extracellular ATP and related nucleotides alter purinergic signalling and inflammasome thresholds ( 26 , 27 ); cardiolipin and mitochondrial reactive oxygen species (ROS) influence inflammasome and redox-sensitive pathways ( 15 , 28 ); and N-formyl peptides regulate chemotaxis through formyl peptide receptors ( 29 , 30 ). We treat these molecules as cooperating modifiers of mtDNA access and interpretation rather than as independent axes. The Review first examines how HCC metabolism and mitochondrial quality control generate structurally distinct mtDNA signals, then follows those signals through compartment-specific sensing and intercellular communication, before integrating them with immune-state transition and therapeutic timing. Direct HCC mechanistic evidence is distinguished from HCC-associated observations, adjacent mechanistic evidence, and the integrative model proposed here. Figure 1 summarises the proposed redox–mtDNA framework, linking mitochondrial danger generation and mtDNA routing to compartment-specific innate sensing, context-dependent interpretation, and signalling states. Figure 1 Redox-driven mitochondrial DNA danger signalling and context-dependent innate immune interpretation in hepatocellular carcinoma. HCC-associated stress promotes mitochondrial dysfunction, nucleoid instability and mtDNA mobilisation into cytosolic, free extracellular, protein-associated and extracellular-vesicle-associated forms. Representative routing–sensor relationships include cytosolic mtDNA–cGAS–STING and endolysosomal mtDNA–TLR9 signalling, whereas oxidised mtDNA contributes to NLRP3 activation together with other activation-associated mitochondrial inputs ( 13 , 15 – 18 , 20 , 21 , 23 , 37 , 38 , 40 , 41 , 44 , 45 ). For visual clarity, only representative routing–sensor relationships are drawn: EV-associated mtDNA can gain cytosolic access after uptake, whereas oxidised mtDNA is represented within NLRP3 Signal 2 rather than by an additional cross-panel arrow. Signal form and packaging, dose, persistence and clearance, recipient-cell competence, redox state and liver context determine whether mitochondrial danger supports a productive, self-limited immune state or maladaptive, persistent immune remodelling. Cooperating mitochondrial DAMPs modify signalling thresholds, and the dashed red feedback route denotes reinforcement of mitochondrial stress by chronic inflammatory and oxidative signalling. To develop this framework, we searched PubMed, Web of Science, and Google Scholar for English-language studies on HCC, redox signalling, mitochondrial stress, mtDNA release and sensing, intercellular communication, and immunotherapy; the search was updated in July 2026. The synthesis prioritises primary mechanistic studies in HCC, followed by HCC-associated evidence and, where direct data are unavailable, mechanistic studies from adjacent disease settings. 2 Upstream redox remodelling and mitochondrial DNA danger signalling in HCC The mitochondrial stress relevant to HCC is rarely an abrupt collapse of organelle function. More often, malignant cells remain viable while compensating for a persistent burden of oxidative and metabolic injury. This partially compensated state permits membrane damage, nucleoid disorganisation, and oxidised mtDNA to accumulate without immediate cell death. The same redox programmes that preserve tumour-cell fitness also alter the responsiveness of neighbouring immune cells, linking signal generation to signal interpretation from the outset. 2.1 Metabolic plasticity and redox imbalance in HCC HCC metabolism cannot be reduced to a binary switch from oxidative phosphorylation (OXPHOS) to glycolysis. Many tumours combine increased glucose uptake, glycolytic flux, lactate production, and extracellular acidification with retained mitochondrial respiration and tricarboxylic acid cycle activity ( 12 , 13 , 31 ). Substrate use changes across oxygen and nutrient gradients and can vary within the same lesion ( 31 , 32 ). For mtDNA biology, the important point is that electron transport continues under fluctuating oxygen availability, oncogenic signalling, and antioxidant demand. The coexistence of glycolytic adaptation and preserved mitochondrial activity creates a sustained but dynamically buffered redox burden. Electron transport, oncogenic signalling, and intermittent hypoxia increase mitochondrial ROS, whereas antioxidant programmes prevent oxidative stress from becoming immediately lethal ( 24 , 28 ). Compensation preserves proliferation but does not necessarily restore organelle integrity. Because mtDNA lies close to the respiratory chain and depends on nucleoid packaging and mitochondrial repair, prolonged oxidative pressure can generate lesions and structural instability in cells that remain metabolically competent ( 15 , 16 ). Lactate, acidosis, and hypoxia also condition the cells that will later encounter mitochondrial material. These factors restrict T- and NK-cell activity, alter macrophage behaviour, promote vascular abnormality, and can increase PD-L1-associated immune restraint ( 33 – 36 ). Their relevance here is not that they require mtDNA sensing, but that they establish different thresholds for interpreting an mtDNA signal. A hypoxic macrophage or dendritic cell is not equivalent to the same cell in a well-perfused, metabolically permissive region. 2.2 Lipid and amino-acid metabolism as redox-buffering stress programmes Lipid and amino-acid metabolism help sustain this compensated state. Lipogenesis, fatty acid oxidation (FAO), glutamine utilisation, and one-carbon metabolism can support membrane synthesis, ATP production, nicotinamide adenine dinucleotide phosphate regeneration, glutathione availability, and biosynthetic flexibility ( 12 , 13 ). Continued FAO and OXPHOS in selected tumours therefore need not indicate metabolic normality; they may instead maintain viability while mitochondrial repair remains incomplete. This adaptation creates a mechanistic paradox. Redox buffering protects tumour cells from acute oxidative death, yet it can prolong the survival of mitochondria that are structurally or functionally compromised. When antioxidant capacity prevents collapse but does not restore membranes, nucleoids, and quality control, oxidised proteins, lipids, and mtDNA persist. Repeated cycles of injury and compensation thus regulate not only tumour growth but also the quantity, molecular form, and timing of mitochondrial danger available for cytosolic displacement or extracellular release ( 13 , 15 ). 2.3 Mitochondrial dynamics, quality control, and mtDNA mobilisation Mitochondrial fusion, fission, and mitophagy normally preserve organelle integrity by redistributing contents, separating damaged regions, and removing mitochondria that cannot recover ( 13 , 15 ). In HCC, dysregulation of mitofusin 1/2, optic atrophy 1, and dynamin-related protein 1 alters mitochondrial morphology and stress tolerance ( 13 ). Fission can support proliferation, but excessive fragmentation increases membrane stress and segregates damaged mitochondrial segments. When mitophagy–lysosomal clearance is incomplete, these segments remain sources of ROS and mtDNA leakage. HCC models directly connect fission-induced mtDNA stress with chemokine-dependent macrophage infiltration and tumour progression ( 37 ), establishing organelle dynamics as an upstream determinant of immune communication. Nucleoid organisation determines whether persistent mitochondrial stress is converted into an accessible DNA signal. Transcription factor A, mitochondrial (TFAM), compacts and protects mtDNA while supporting replication and transcription ( 15 , 38 ). Oxidative injury, altered dynamics, or reduced TFAM protection can loosen nucleoid architecture and facilitate mtDNA oxidation, fragmentation, and displacement. In HCC cells, TFAM downregulation increases cytosolic mtDNA and NLRP3-associated cytokine signalling, linking a tumour-cell-intrinsic defect in nucleoid maintenance to macrophage recruitment and tumour progression ( 23 ). This evidence supports TFAM-dependent mobilisation in HCC, but not the assumption that every oxidised or fragmented mtDNA species follows the same route. Mechanistic studies outside HCC identify several non-exclusive routes by which displaced mtDNA crosses mitochondrial membranes, spanning sublethal leakage and cell-death-associated permeabilisation. During mitochondrial apoptosis, BAX/BAK-dependent outer-membrane permeabilisation can generate large macropores that permit inner-membrane herniation and mtDNA efflux ( 39 ). In oxidatively stressed non-apoptotic cells, oligomerised voltage-dependent anion channels (VDACs) form pores that release short mtDNA fragments ( 40 ). In activated macrophages, mitochondrial permeability transition pore (mPTP) opening can promote VDAC oligomerisation and the release of oxidised fragments that subsequently engage NLRP3 or cGAS–STING ( 41 ). Mitochondrial-derived vesicles and defective mitophagy provide additional routes in other experimental settings ( 15 , 38 ). Together, these observations indicate that mtDNA mobilisation is not restricted to a single cellular state: viable stressed cells and dying cells can expose mitochondrial genomes through partly distinct mechanisms. Their relative contributions in HCC remain unresolved. Once mtDNA reaches the cytosol or extracellular space, packaging becomes an upstream determinant of receptor access rather than a passive consequence of release. mtDNA may remain as cytosolic fragments, circulate freely, associate with TFAM or other proteins, or be protected within extracellular vesicles ( 15 , 38 ). Free extracellular mtDNA is vulnerable to degradation and can reflect injury to tumour cells or non-malignant hepatocytes ( 15 , 42 ). Protein association and vesicular encapsulation alter persistence, uptake, and recipient-cell selectivity. In HCC, hypoxic tumour cells transfer vesicle-associated mtDNA to macrophages ( 20 ), whereas treatment-associated injury can increase extracellular mtDNA available for macrophage endocytosis and TLR9 signalling ( 21 ). Signal architecture is therefore established before sensor selection: oxidation and fragmentation influence molecular reactivity, while packaging and trafficking determine which cellular compartment encounters the signal. 2.4 Redox signalling as a dual regulator of innate immune responses ROS are signalling molecules as well as mediators of molecular damage. Changes in redox state alter cysteine-dependent kinases and phosphatases, receptor-proximal signalling, transcription-factor activation, and the metabolic programmes that support innate immune responses ( 24 , 25 , 28 ). Redox remodelling has two linked effects: it promotes mitochondrial and nucleoid injury, and it modifies the signalling thresholds of cells that generate or receive mtDNA. This dual action explains why mtDNA abundance alone is an incomplete predictor of immune outcome. Recipient-cell competence is particularly important for interferon and NF-κB outputs. In plasmacytoid dendritic cells, mitochondria-derived ROS and metabolic checkpoints regulate TLR7/9-associated type I interferon responses ( 43 ). More broadly, redox-sensitive signalling influences STING- and TLR-associated kinase activity, interferon responsiveness, and NF-κB-dependent transcription ( 24 , 25 ). A dendritic cell with intact interferon and antigen-processing programmes may translate nucleic-acid exposure into maturation and cross-presentation, whereas a macrophage conditioned by tumour-derived cytokines may favour persistent NF-κB activity and suppressive differentiation. In HCC, direct evidence centres on the diver
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