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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.<\/jats:p>","DOI":"10.1038\/s41388-025-03641-4","type":"journal-article","created":{"date-parts":[[2025,11,23]],"date-time":"2025-11-23T08:11:29Z","timestamp":1763885489000},"page":"4846-4854","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["A selective RPL15 PROTAC degrader enhances anti-PD-1 immunotherapy in a murine melanoma tumor model"],"prefix":"10.1038","volume":"44","author":[{"given":"Runa","family":"Takahashi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kazuki","family":"Yamamoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hikaru","family":"Toya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Shoji","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kohei","family":"Kawanishi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyoka","family":"Momosaki","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miyuki","family":"Yabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2194-1426","authenticated-orcid":false,"given":"Ken","family":"Takashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryuta","family":"Muromoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5345-5007","authenticated-orcid":false,"given":"Satoshi","family":"Ichikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tadashi","family":"Matsuda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5998-3855","authenticated-orcid":false,"given":"Yuichi","family":"Kitai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,23]]},"reference":[{"key":"3641_CR1","doi-asserted-by":"publisher","first-page":"12293","DOI":"10.1073\/pnas.192461099","volume":"99","author":"Y Iwai","year":"2002","unstructured":"Iwai Y, Ishida M, Tanaka Y, Okazaki T, Honjo T, Minato N. 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