Academic Journal
Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications.
| Τίτλος: | Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications. |
|---|---|
| Συγγραφείς: | Chang Z; Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, China., Liu G; Emergency Department, The Affiliated Hospital of Yanbian University, Yanji, China., Zhang J; Department of Metabolic and Bariatric Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, China., Lei H; Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, China., Quan H; Central Laboratory, The Affiliated Hospital of Yanbian University, Yanji, China., Piao Y; Emergency Department, The Affiliated Hospital of Yanbian University, Yanji, China. |
| Πηγή: | Frontiers in immunology [Front Immunol] 2026 Sep 04; Vol. 17, pp. 1903643. Date of Electronic Publication: 2026 Sep 04 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article; Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| Ιατρικοί όροι (MeSH): | DNA, Mitochondrial*/genetics , DNA, Mitochondrial*/immunology , DNA, Mitochondrial*/metabolism , Carcinoma, Hepatocellular*/immunology , Carcinoma, Hepatocellular*/therapy , Carcinoma, Hepatocellular*/metabolism , Carcinoma, Hepatocellular*/genetics , Carcinoma, Hepatocellular*/pathology , Liver Neoplasms*/immunology , Liver Neoplasms*/therapy , Liver Neoplasms*/metabolism , Liver Neoplasms*/genetics , Liver Neoplasms*/pathology , Tumor Escape*/immunology , Immunity, Innate*, Mitochondria/metabolism ; Mitochondria/immunology ; Mitochondria/genetics ; Reactive Oxygen Species/metabolism ; Humans ; Oxidation-Reduction ; Animals ; Immunotherapy ; Oxidative Stress ; cGAS-STING Signaling Pathway ; Toll-Like Receptor 9 ; DNA Damage ; Signal Transduction ; Innate Immunity Recognition |
| Περίληψη: | 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. (Copyright © 2026 Chang, Liu, Zhang, Lei, Quan and Piao.) |
| Competing Interests: | The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
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| Contributed Indexing: | Keywords: hepatocellular carcinoma; immunotherapy; innate immunity; mitochondrial DNA; mitochondrial danger signals; redox signalling; tumour immune escape; tumour immune microenvironment |
| Substance Nomenclature: | 0 (DNA, Mitochondrial) 0 (Toll-Like Receptor 9) 0 (Reactive Oxygen Species) |
| Entry Date(s): | Date Created: 20260919 Date Completed: 20260919 Latest Revision: 20260921 |
| Update Code: | 20260921 |
| PubMed Central ID: | PMC13587012 |
| DOI: | 10.3389/fimmu.2026.1903643 |
| PMID: | 42761405 |
| Βάση Δεδομένων: | MEDLINE |
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