10.5283/epub.79407ArticleHarrer, Dennis ChristophDennis ChristophHarrer0000-0001-7512-572XHaferkamp, SebastianSebastianHaferkamp0000-0002-3894-8345Herr, WolfgangWolfgangHerrMycielska, Maria E.Maria E.Mycielska0000-0001-5222-256XDörrie, JanJanDörrieSchaft, NielsNielsSchaftAbken, HinrichHinrichAbken0000-0002-4302-3240Drexler, KonstantinKonstantinDrexler0009-0004-6601-6299Universität Regensburg2026CAR-T cell; adoptive T cell therapy; gluconate; citrate; melanoma; tumor microenvironment610 MedizinBackground: Chimeric antigen receptor (CAR) T cells achieve cure in the therapy of hematological malignancies. In solid tumors, however, CAR-T cells face an immunosuppressive tumor microenvironment (TME) which crucially impedes their cytotoxic capacities. Citrate accumulating in the TME is a crucial metabolite in mediating immune suppression and is consumed by cancer cells promoting growth of various tumors, including melanoma; blocking the citrate transporter pmCiC with gluconate abrogates citrate-mediated tumor growth. Methods: To bolster treatment of melanoma, we explored gluconate as adjuvant for CAR-T cell therapy. Results: First, gluconate did not impair CAR-T cell functional capacities with regard to cytotoxicity, cytokine secretion, and persistence in a “stress test” based on repetitive antigen stimulation with cognate cancer cells. The addition of gluconate antagonized the citrate-mediated enhanced proliferation of melanoma cells. As a consequence, the elimination of citrate-boosted melanoma cells by CSPG4-specific CAR-T cells was augmented in the presence of gluconate. Conclusions: Taken together, these data suggest that counteracting citrate-mediated enhanced tumor growth with gluconate may improve the cytotoxic activity of CAR-T cells against melanoma.https://epub.uni-regensburg.de/79407/urn:nbn:de:bvb:355-epub-794074http://doi.org/10.3390/pharmaceutics1805055110.3390/pharmaceutics18050551