A selective RPL15 PROTAC degrader enhances anti-PD-1 immunotherapy in a murine melanoma tumor model

  • Oncogene. 2025 Dec;44(50):4846-4854. doi: 10.1038/s41388-025-03641-4.
Runa Takahashi  #  1 ,  Kazuki Yamamoto  #  2 ,  Hikaru Toya  3 ,  Haruka Shoji  1 ,  Kohei Kawanishi  2 ,  Kyoka Momosaki  2 ,  Miyuki Yabe  2 ,  Ken Takashima  4 ,  Ryuta Muromoto  5 ,  Satoshi Ichikawa  2  6  7 ,  Tadashi Matsuda  8 ,  Yuichi Kitai  9  10
Affiliations
  • 1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan.
  • 2. Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
  • 3. RNA Biology Laboratory, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
  • 4. Department of Immunology, Faculty of Life Sciences, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
  • 5. Laboratory of Microbiology and Immunology, Graduate School of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan.
  • 6. Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
  • 7. Global Station for Biosurfaces and Drug Discovery, Global Institution for Collaborative Research and Education (GI-CoRE), Hokkaido University, Sapporo, Japan.
  • 8. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan. [email protected].
  • 9. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Hokkaido, Japan. [email protected].
  • 10. Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Japan. [email protected].
  • # Contributed equally.
PMID: 41276688 DOI: 10.1038/s41388-025-03641-4
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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