恶性肿瘤常通过抑制T淋巴细胞的细胞毒功能来逃避抗癌免疫监视。虽然许多免疫逃脱网络包括检查点蛋白，但小分子量化合物，如氨基酸L-酪氨酸（LKU），也可以显著促进抗癌免疫的抑制。然而，LKU对T细胞功能的抑制作用的生化机制尚不清楚。在这里，我们首次报告LKU作为芳香族羟基化酶（AhR）配体抑制T细胞功能的情况。LKU存在于T细胞中与AhR激活相关，这导致AhR和缺氧诱导因子1α（HIF-1α）之间在AhR核转运子ARNT上竞争，导致T细胞耗竭。转化生长因子β-Smad-3途径诱导色胺酸2,3-二加氧酶1（IDO1，导致LKU产生的酶）的表达。我们还展示IDO阴性癌症通过内源性炎症介质高迁移率族聚盒1（HMGB-1）-干扰素γ（IFN-γ）轴的另一途径进行LKU的产生。此外，其他IDO阴性肿瘤（如T细胞淋巴瘤）在肿瘤微环境（TME）中触发嗜酸性粒细胞中IDO1的激活。这些机制抑制了细胞毒性T细胞功能，从而支持肿瘤免疫逃避机制。© 2023 作者。以Taylor & Francis Group, LLC许可证发表。

Malignant tumors often escape anticancer immune surveillance by suppressing the cytotoxic functions of T lymphocytes. While many of these immune evasion networks include checkpoint proteins, small molecular weight compounds, such as the amino acid L-kynurenine (LKU), could also substantially contribute to the suppression of anti-cancer immunity. However, the biochemical mechanisms underlying the suppressive effects of LKU on T-cells remain unclear. Here, we report for the first time that LKU suppresses T cell function as an aryl hydrocarbon receptor (AhR) ligand. The presence of LKU in T cells is associated with AhR activation, which results in competition between AhR and hypoxia-inducible factor 1 alpha (HIF-1α) for the AhR nuclear translocator, ARNT, leading to T cell exhaustion. The expression of indoleamine 2,3-dioxygenase 1 (IDO1, the enzyme that leads to LKU generation) is induced by the TGF-β-Smad-3 pathway. We also show that IDO-negative cancers utilize an alternative route for LKU production via the endogenous inflammatory mediator, the high mobility group box 1 (HMGB-1)-interferon-gamma (IFN-γ) axis. In addition, other IDO-negative tumors (like T-cell lymphomas) trigger IDO1 activation in eosinophils present in the tumor microenvironment (TME). These mechanisms suppress cytotoxic T cell function, and thus support the tumor immune evasion machinery.© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.