Cisplatin reduces immunosuppression caused by tumor-associated macrophages through downregulating CD47-SIRPα signaling in glioblastoma

The poor prognosis of glioblastoma (GBM) is partly attributed to the immunosuppressive microenvironment. The combination of standard temozolomide and other chemotherapy drugs can significantly enhance the therapeutic effect by reshaping the immune microenvironment. Cisplatin treatment induces immunogenic cell death in tumor cells, stimulating an immune response. Here, we investigated the immune-activating effect of cisplatin on tumor-associated macrophages (TAMs). The therapeutic benefit of temozolomide plus cisplatin was showed in a murine model of GBM, accompanied by the inhibition of tumor growth and enhancement of pro-inflammatory activation of TAMs. Furthermore, cisplatin treatment downregulated the expression of CD47 in glioma stem cells, SIRPα, and IL-6 in TAMs, thus promoting M1-like polarization of TAMs to enhance an immune-activating tumor microenvironment. Mechanically, cisplatin decreases the production of lactic acid by downregulating LDHA expression. A low level of lactate reduces histone H3K18 lactylation on the CD47 and IL-6 promoters, thereby suppressing gene transcription. Our study reveals a new mechanism by which cisplatin remodels the immune tumor microenvironment, suggesting that combining temozolomide with cisplatin chemotherapy may be a new treatment option for GBM.