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bioRxiv · 10.1101/2025.04.17.649282

Isoform switch of CD47 provokes macrophage-mediated pyroptosis in ovarian cancer

Wang, Z.·Yang, L.·Yang, S.·Li, G.·Xu, M.·Kong, B.·Shao, C.·Liu, Z.
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Abstract

Cancer cells expressing CD47 escape macrophage phagocytosis by binding to the SIRP ligand expressed on macrophages. CD47 targeted therapy offers a promising approach to cancer treatment. Here we report that two major isoforms of CD47 differ in ovarian cancer and normal tissues. The truncated isoform lacking exon 9 and exon 10 (CD47-S) was exclusively expressed in normal tissues, whereas the full-length isoform (CD47-L) was predominantly expressed in ovarian cancer tissues. Interestingly, CD47-S was unable to locate at the cell surface to bind with SIRP as CD47-L did, and thereby inactivated "dont-eat-me" signal. Mechanistic investigations revealed that splicing factor HNRNPA1 promoted splicing switch from CD47-L to CD47-S through exon 9 and exon 10 skipping. We further developed antisense oligonucleotides (ASOs) that effectively switched CD47-L to CD47-S. Importantly, ASOs treatment evoked macrophage-mediated antitumor immune response, thereby triggered pyroptosis of ovarian cancer cells. Moreover, CD47-targeting ASOs significantly reduced tumor growth in patient-derived xenograft. Together, ASO-mediated isoform switch of CD47 has emerged as a promising strategy to improve immune responses against tumors.

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Wang, Z., Yang, L., Yang, S., Li, G., Xu, M., Kong, B., Shao, C., Liu, Z.. 2025-04-18. Isoform switch of CD47 provokes macrophage-mediated pyroptosis in ovarian cancer. https://doi.org/10.1101/2025.04.17.649282

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