Sphingosine kinase 1 promotes tumor immune evasion by regulating the MTA3-PD-L1 axis
Why this work is in the frame
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Bibliographic record
Abstract
Immune checkpoint blockade (ICB) exhibits considerable benefits in malignancies, but its overall response rate is limited. Previous studies have shown that sphingosine kinases (SPHKs) are critical in the tumor microenvironment (TME), but their role in immunotherapy is unclear. We performed integrative analyses including bioinformatics analysis, functional study, and clinical validation to investigate the role of SPHK1 in tumor immunity. Functionally, we demonstrated that the inhibition of SPHK1 significantly suppressed tumor growth by promoting antitumor immunity in immunocompetent melanoma mouse models and tumor T-cell cocultures. A mechanistic analysis revealed that MTA3 functions as the downstream target of SPHK1 in transcriptionally regulating tumor PD-L1. Preclinically, we found that anti-PD-1 monoclonal antibody (mAb) treatment significantly rescued tumor SPHK1 overexpression or tumor MTA3 overexpression-mediated immune evasion. Significantly, we identified SPHK1 and MTA3 as biological markers for predicting the efficacy of anti-PD-1 mAb therapy in melanoma patients. Our findings revealed a novel role for SPHK1 in tumor evasion mediated by regulating the MTA3-PD-L1 axis, identified SPHK1 and MTA3 as predictors for assessing the efficacy of PD-1 mAb treatment, and provided a therapeutic possibility for the treatment of melanoma patients.
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Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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 | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 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 it