Targeting tumor-infiltrating regulatory T cells: combining CD47 and PD-L1 inhibition via a novel aptamer-siRNA chimera
Bibliographic record
Abstract
Tumor-infiltrating regulatory T (Treg) cells contribute to immune evasion and are associated with poor prognosis in solid tumors. While CD47 blockade has demonstrated efficacy in hematologic malignancies, its application in solid tumors is hindered by the antigen sink effect and lack of tumor selectivity. Here, we report a rationally designed aptamer-siRNA chimera that selectively targets intratumoral Treg cells by exploiting their co-expression of PD-L1 and CD47 within the tumor microenvironment. The PD-L1 aptamer enables selective binding to PD-L1⁺ Treg cells and simultaneously inhibits PD-L1-mediated immune suppression. Conjugated CD47 siRNA silences CD47 expression, abrogating the "don't eat me" signal and facilitating phagocytic clearance. Mechanistically, this chimera efficiently depletes tumor-infiltrating Treg cells with negligible impact on peripheral cells, and leads to a pronounced increase in intratumoral CD8⁺ T cell infiltration. Further investigation revealed that the chimera impairs Treg migration by disrupting glycolysis-related signaling pathways, including pERK1/2 and pRac1, and induces metabolic reprogramming characterized by reduced glycolysis, increased oxidative metabolism, and elevated fatty acid oxidation (FAO). In murine hepatocellular carcinoma models, treatment with the chimera significantly inhibited tumor growth, reduced angiogenesis, and prolonged survival. Our findings highlight a dual immune checkpoint-targeting strategy that integrates selective delivery with gene silencing, offering a tumor-specific, non-antibody approach for Treg depletion and a promising avenue for solid tumor immunotherapy.
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How this classification was reachedexpand
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 | 0.000 | 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 | 0.000 |
| 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 itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, 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".