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

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-P

SUBMITTER: Takahashi R 

PROVIDER: S-EPMC12669025 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature