biostudies-literatureKay KECancer Council VictoriaVictorian Cancer AgencyNHLBI NIH HHSNCI NIH HHSNational Health and Medical Research CouncilPerpetualNINDS NIH HHSNational Institutes of HealthNIGMS NIH HHSe177824https://www.ebi.ac.uk/biostudies/studies/S-EPMC11735101biostudies-literatureUnknown135(2)The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly affect the immune system, but the mechanisms driving these interactions are not completely clear. Here, we demonstrate that the polyamine metabolite spermidine (SPD) was elevated in the GBM tumor microenvironment. Exogenous administration of SPD drove tumor aggressiveness in an immune-dependent manner in preclinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in SPD synthesis, did not affect cancer cell growth in vitro but did result in extended survival. Furthermore, patients with GBM with a more favorable outcomeThe Journal of clinical investigationTumor cell-derived spermidine promotes a protumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.PMC11735101IPAP20221259F31 CA264849MCRF22003VG2022T32 GM007250F31 CA264849,T32 GM088088,R35 NS127083,P01 CA245705,K99 CA248611,R01HL103866,P01HL147823R35 NS127083T32 GM088088R01 HL103866P01 CA245705P01 HL147823GNT1184421K99 CA248611Wang SZHong ESLee JJohnson SHazen SLSilver DJBest SAWang ZKay KEDayal SWesley ERNarayana VMitchell SReizes OBeilis JBrown JMFreytag SWhittle JRYu JSVolovetz JLu TFreytag LMcGraw MBayik DLathia JDGrabowski MMfalseTumor cell-derived spermidine promotes a protumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition.The glioblastoma (GBM) microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly affect the immune system, but the mechanisms driving these interactions are not completely clear. Here, we demonstrate that the polyamine metabolite spermidine (SPD) was elevated in the GBM tumor microenvironment. Exogenous administration of SPD drove tumor aggressiveness in an immune-dependent manner in preclinical mouse models via reduction of CD8+ T cell frequency and reduced cytotoxic function. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in SPD synthesis, did not affect cancer cell growth in vitro but did result in extended survival. Furthermore, patients with GBM with a more favorable outcome2024-01-01T00:00:00Z2024 Nov2026-06-03T01:15:29.469Z2025-04-06T01:16:15.965ZS-EPMC117351013956101210.1172/JCI177824