biostudies-literatureUnknown27(5)Bopp LDeutsche ForschungsgemeinschaftMichael Smith Foundation for Health ResearchT cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8⁺ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers <i>c-MYC</i> and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ expiScience109767https://www.ebi.ac.uk/biostudies/studies/S-EPMC11088342biostudies-literatureGlutamine promotes human CD8⁺ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.PMC11088342Brodesser SMartinez MLLackmann JWBopp LLukas DArana MHOh JHBrachvogel BSeitz RNeumayer DKlapproth HMueller Svon Stebut EKlein Geltink RISchumacher CFabri MfalseGlutamine promotes human CD8⁺ T cells and counteracts imiquimod-induced T cell hyporesponsiveness.T cells protect tissues from cancer. Although investigations in mice showed that amino acids (AA) critically regulate T cell immunity, this remains poorly understood in humans. Here, we describe the AA composition of interstitial fluids in keratinocyte-derived skin cancers (KDSCs) and study the effect of AA on T cells using models of primary human cells and tissues. Gln contributed to ∼15% of interstitial AAs and promoted interferon gamma (IFN-γ), but not granzyme B (GzB) expression, in CD8⁺ T cells. Furthermore, the Toll-like receptor 7 agonist imiquimod (IMQ), a common treatment for KDSCs, down-regulated the metabolic gatekeepers <i>c-MYC</i> and mTORC1, as well as the AA transporter ASCT2 and intracellular Gln, Asn, Ala, and Asp in T cells. Reduced proliferation and IFN-γ exp2024-01-01T00:00:00Z2024 May2026-06-03T04:21:43.441Z2026-04-24T03:10:00.176ZS-EPMC110883423873654510.1016/j.isci.2024.109767