Redox-driven mitochondrial DNA stress in hepatocellular carcinoma: innate immune remodelling, tumour immune escape, and immunotherapy implications

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.