Metabolic reprogramming of antitumor CD8+ T cells by modulation of GSH-Gpx4 axis
Bibliographic record
Abstract
Abstract The CD8+ T cells within tumor microenvironment are the most essential component in tumor immunity. Activation of CD8+ T cells is coupled to various metabolic reprogramming. Glutathione (GSH) as the key role in oxidative metabolismto buffer increased reactive oxygen species (ROS) in activated T cells, is important for T cells effector functions in the context of inflammation. The function and mechanism by GSH metabolism in regulating anti-tumor immunity of CD8+ T cells remain unknown. Here, we show that GSH is dependent on glutathione peroxidase 4 (Gpx4) to maintain CD8+ T cell activity, and A2AR signaling pathway interacts with the GSH-Gpx4 axis to reprogram the metabolism and survival of functional CD8+ T cells. Interestingly, A2AR signaling blockade increases effector function of antitumor CD8+ T cells, but facilitates the assumption of intracellular GSH, leading to rapid ferroptosis. Notably, combination treatment with a potent ferroptosis inhibitor liproxstatin-1 (Lip-1) and A2AR antagonists elicits a synergistic antitumor efficacy and enhanced mitochondrial functionality of antitumor CD8+ T cells in multiple mouse tumor models. Finally, we generate a gene expression signature for GSH metabolism in tumor-infiltrating CD8+ T cells positively correlating with favorable clinical outcomes. Our work demonstrate a critical role of GSH metabolism in modulating antitumor CD8+ T cell survival and functionality, pointing to new strategies of targeting these cells for cancer immunotherapy.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".