STING synergizes with TOX suppressing HO-1 expression to trigger ferroptosis in tumor-infiltrating CD8+ T cell and immunotherapy resistance - PubMed
3 months ago
- #immunotherapy
- #CD8+ T cells
- #ferroptosis
- STING and TOX synergize to suppress HO-1 expression, triggering ferroptosis in tumor-infiltrating CD8+ T cells and leading to immunotherapy resistance.
- CD8+ T cells lacking STING or TOX show improved antitumor activity, with increased tumor infiltration and higher production of IFN-γ and granzyme B.
- STING and TOX deficient CD8+ T cells resist ferroptosis by suppressing lipid peroxidation and promoting mitochondrial biogenesis.
- STING and TOX form a positive regulatory loop that represses HO-1, causing iron accumulation, mitochondrial oxidative stress, and ferroptosis in CD8+ T cells.
- Lactate is identified as a microenvironmental trigger for STING-TOX-HO-1-mediated CD8+ T-cell ferroptosis.
- Engineered STING/TOX-deficient CD8+ T cells enhance tumor control when combined with immune checkpoint blockade, chemotherapy, or STING agonists in mouse models.