ArticleOncogene2025
A selective RPL15 PROTAC degrader enhances anti-PD-1 immunotherapy in a murine melanoma tumor model.
Article in Oncogene, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers, 1 of them a synthesis that pooled it.
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
2 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pooled it
- PROTAC-based protein degradation: a window of opportunity for melanoma therapy.Journal of biomedical science · 2026Review
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Authors and funding
12 authors.
Funding
Abstract
Damage-associated molecular patterns (DAMPs) are secreted from damaged or dying cells and activate innate immune signaling via pattern-recognition receptors such as Toll-like receptors and cGAS. We previously showed that topotecan, a chemotherapeutic drug and topoisomerase I (TOP1) inhibitor, binds to ribosomal protein RPL15 and induces the secretion of DAMPs from cancer cells, which activate cGAS-STING signaling in dendritic cells. RPL15-knockdown B16-F10 melanoma tumors were sensitized to anti-PD-1 antibody, suggesting that RPL15 inhibition may have the potential to improve immune checkpoint inhibitor efficacy. However, topotecan and its derivatives, including SN-38, are highly cytotoxic because of their TOP1 inhibitory activity. Here, we synthesized SN-38-conjugated pomalidomide (SN38-PROTAC) and showed that SN38-PROTAC induced ubiquitin-mediated degradation of RPL15, but not TOP1. SN38-PROTAC treatment induced DAMP secretion from cancer cells, which activated cGAS-STING signaling in dendritic cells. The cytotoxicity of SN38-PROTAC in MCF7 cells was 100-fold lower than SN-38. SN38-PROTAC treatment increased the CTL/Treg ratio in tumors and sensitized B16-F10 tumors to anti-PD-1 antibody in a mouse model. The enhanced antitumor effects of SN38-PROTAC and anti-PD-1 antibody combination were abolished in STING-deficient mice. Our results indicate that SN38-PROTAC, which induces RPL15 degradation, has the potential to enhance ICI efficacy in PD-1-resistant cancer with low cytotoxicity.
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Registered trials
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