Isoform switching of CD47 induces macrophage-initiated cancer cell pyroptosis

Cancer cells escape immunosurveillance by expressing CD47, which binds to the SIRPα ligand on the surface of macrophages. Thus, CD47-targeted therapy represents a promising approach to overcoming cancer immune tolerance. Here we report that two major isoforms of CD47 exhibit distinct expression patterns in ovarian cancer and normal tissues. Single-cell and spatial transcriptome data analysis showed that the microexon skipped isoform (CD47-S) was preferentially expressed in normal tissues, whereas the full-length isoform (CD47-L) was predominantly expressed in ovarian cancer tissues and its expression was associated with an immunosuppressive tumor microenvironment. Mechanistically, the splicing factor HNRNPA1 was downregulated in ovarian cancer, resulting in the predominance of CD47-L . Importantly, antisense oligonucleotides (ASOs) that switch CD47-L to CD47-S effectively evoked pyroptosis as well as phagocytosis of cancer cells. Moreover, CD47-targeting ASOs significantly reduced tumor growth in patient-derived xenografts. Taken together, this study reveals an alternative splicing-based regulation of CD47 function and demonstrates ASO-mediated isoform switching of CD47 as a promising strategy for improving immune responses against tumors while avoiding the hematotoxicity associated with anti-CD47 antibodies.