Abstract A017: Non-canonical CD47 enhances cardiolipin biosynthesis and remodeling in Temozolomide-resistant establishment and reduces microglia-mediated cytotoxicity in glioblastoma progression

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Abstract Glioblastoma (GBM) is the most malignant brain tumor, characterized by frequent resistance to standard therapy, Temozolomide (TMZ), which is highly related to GBM metabolic rewiring. The transmembrane protein CD47 is known for its role in innate immune suppression by binding to SIRPα on myeloid cells. However, non-canonical CD47 pathway activated by thrombospondin 1 (TSP1) suggests a different role for CD47 in tumor progression, and whether this signaling axis modulates GBM metabolism remains unclear. Our patient biopsy data revealed strong CD47 immunoreactivity in GBM compared with adjacent normal tissue (n=21, p < 0.05). Paired (recurrent/primary) GBM patient RNA-Seq (n=14) shows that CD47 is upregulated in recurrent tumors, and high CD47 levels, along with high TSP1 expression in TCGA GBM database, are associated with poor survival, suggesting the importance of the non-canonical CD47 pathway in GBM. In CD47-overexpressing GBM cells, RNA-Seq revealed enrichment of OXPHOS, fatty acid metabolism, and phospholipid synthesis. Lipidomics confirmed CD47-driven upregulation of cardiolipin (CL), suggesting metabolic rewiring via non-canonical CD47 signaling. Patient tumors and TMZ-resistant GBM cells similarly showed induction of CL biosynthesis and remodeling enzymes, which regulate mitochondrial function by incorporating fatty acids. The key enzyme of monounsaturated FA (MUFA) synthesis, Stearoyl-CoA Desaturase, is increased in recurrent tumors. MUFA-CL is studied to promote stable and efficient mitochondrial respiration, whereas polyunsaturated FA (PUFA)-CL is prone to damage by mitochondrial stress. We found that GBM cells pretreated with MUFA oleate increased the mitochondrial spare capacity compared to PUFA linoleic acid incubation. Further, we showed that TSP1 activates CL processing in GBM cells and suggested that the non-canonical CD47 pathway may promote TMZ resistance by increasing MUFA-CL to prevent TMZ-induced mitochondrial stress. Interestingly, CD47 knockdown using different shRNAs showed distinct gene enrichments between metabolism and immune phagocytosis. Also, anti-sense morpholinos targeting CD47 (CD47M) reduced FA-dependent mitochondrial respiration and the activity of key enzymes involved in CL processing in GBM cells. Moreover, TMZ combined with CD47M significantly reduced the GBM viability. On the other hand, we found that targeting non-canonical CD47 on microglia produced the opposite effect to that in cancer cells, with increased OXPHOS and FA metabolism. This alteration significantly increases microglia-mediated killing of GBM. Further, human GBM organoids showed that CD47M pre-treated microglia increased organoid transparency, indicating increased microglial cytotoxicity toward patient-derived GBM cells. Taking together, our data suggests that targeting the non-canonical CD47 pathway may be a potential approach for TMZ-resistant GBM and enhance microglia-mediated cytotoxicity. Citation Format: Yu-Ting Tsai, Mitra Kooshki, Jamie Sagastume, Valerie Payne, Ashley Szymonski, Pin-Yuan Chen, Jian-Ying Chuang, Tsung-I Hsu, Shay Soker, Glenn Lesser, David Soto-Pantoja. Non-canonical CD47 enhances cardiolipin biosynthesis and remodeling in Temozolomide-resistant establishment and reduces microglia-mediated cytotoxicity in glioblastoma progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A017.

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