{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Jin S"],"funding":["National Natural Science Foundation of China","the Key Scientific Research Projects of Higher Education Institutions in Henan Province","the Project of Henan Province"],"pagination":["173"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC10926604"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["22(1)"],"pubmed_abstract":["<h4>Background</h4>Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative.<h4>Methods</h4>SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model.<h4>Results</h4>SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8<sup>+</sup> T and M1-type macrophages into tumor sites, while also priming the function of CD8<sup>+</sup> T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy.<h4>Conclusion</h4>Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy."],"journal":["Cell communication and signaling : CCS"],"pubmed_title":["Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy."],"pmcid":["PMC10926604"],"funding_grant_id":["U1904147","82002575","232102311172","22A180029","U20A20369","82272785"],"pubmed_authors":["Yang J","Wu M","Jin S","Shi P","Zhao W","Wang H","Zhou X","Niu X","Li Y","Zhai W","Zhang X","Qi Y","Gao Y","Li B","Wu Y"],"additional_accession":[]},"is_claimable":false,"name":"Discovery of a novel small molecule as CD47/SIRPα and PD-1/PD-L1 dual inhibitor for cancer immunotherapy.","description":"<h4>Background</h4>Targeting the tumor microenvironment (TME) has emerged as a promising strategy in cancer treatment, particularly through the utilization of immune checkpoint blockade (ICB) agents such as PD-1/PD-L1 inhibitors. Despite partial success, the presence of tumor-associated macrophages (TAMs) contributes to an immunosuppressive TME that fosters tumor progression, and diminishes the therapeutic efficacy of ICB. Blockade of the CD47/SIRPα pathway has proven to be an effective intervention, that restores macrophage phagocytosis and yields substantial antitumor effects, especially when combined with PD-1/PD-L1 blockade. Therefore, the identification of small molecules capable of simultaneously blocking CD47/SIRPα and PD-1/PD-L1 interactions has remained imperative.<h4>Methods</h4>SMC18, a small molecule with the capacity of targeting both SIRPα and PD-L1 was obtained using MST. The efficiency of SMC18 in interrupting CD47/SIRPα and PD-1/PD-L1 interactions was tested by the blocking assay. The function of SMC18 in enhancing the activity of macrophages and T cells was tested using phagocytosis assay and co-culture assay. The antitumor effects and mechanisms of SMC18 were investigated in the MC38-bearing mouse model.<h4>Results</h4>SMC18, a small molecule that dual-targets both SIRPα and PD-L1 protein, was identified. SMC18 effectively blocked CD47/SIRPα interaction, thereby restoring macrophage phagocytosis, and disrupted PD-1/PD-L1 interactions, thus activating Jurkat cells, as evidenced by increased secretion of IL-2. SMC18 demonstrated substantial inhibition of MC38 tumor growths through promoting the infiltration of CD8<sup>+</sup> T and M1-type macrophages into tumor sites, while also priming the function of CD8<sup>+</sup> T cells and macrophages. Moreover, SMC18 in combination with radiotherapy (RT) further improved the therapeutic efficacy.<h4>Conclusion</h4>Our findings suggested that the small molecule compound SMC18, which dual-targets the CD47/SIRPα and PD-1/PD-L1 pathways, could be a candidate for promoting macrophage- and T-cell-mediated phagocytosis and immune responses in cancer immunotherapy.","dates":{"release":"2024-01-01T00:00:00Z","publication":"2024 Mar","modification":"2026-07-01T03:14:47.714Z","creation":"2025-04-07T10:44:05.544Z"},"accession":"S-EPMC10926604","cross_references":{"pubmed":["38462636"],"doi":["10.1186/s12964-024-01555-4"]}}