Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.

色氨酸（Trp）分解代谢物激活芳烃受体（AHR）可增强肿瘤恶性程度并抑制抗肿瘤免疫力。迄今为止，AHR靶基因的背景特异性阻碍了AHR活性及其跨人类癌症的上游酶的系统研究。甲泛组织AHR签名，通过自然语言处理中导出，发现，在32个肿瘤实体，白细胞介素4诱导-1（IL4I1）关联更频繁比AHR活性IDO1或TDO2，迄今公认是主要的Trp分解酶。IL4I1通过生成吲哚代谢产物和犬尿酸来激活AHR。它与神经胶质瘤患者的生存期缩短，促进癌细胞运动并抑制适应性免疫有关，从而增强了小鼠慢性淋巴细胞性白血病（CLL）的进程。免疫检查点封锁（ICB）诱导IDO1和IL4I1。由于IDO1抑制剂不会阻断IL4I1，因此IL4I1可能解释了ICB与IDO1抑制相结合的临床研究失败。总之，IL4I1阻断剂为癌症治疗开辟了新途径。