A plethora of previous studies have been focused on the role of indoleamine 2,3-dioxygenase 1 (IDO1) in cancer immunity; however, the alternative way of targeting tryptophan 2,3-dioxygenase (TDO2) in cancer immunotherapy has been largely ignored. In particular, the specific role of TDO2 in breast cancer remains unclear. In the present study, we systematically explored and validated the expression and prognostic value of TDO2 in breast cancer using large-scale transcriptome data. We observed overexpression of TDO2 in many types of cancer tissues compared with adjacent normal tissues. TDO2 overexpression was revealed to be positively correlated with malignancy and tumor grade in breast cancer. TDO2 expression was higher in estrogen-negative breast cancer and triple-negative breast cancer, and it was correlated with worse outcome in breast cancer patients. TDO2 expression was correlated with immune infiltrates and tryptophan metabolism-related genes (IDO1 and kynureninase [KYNU]). Therefore, our results indicated that TDO2 plays a pivotal role in regulating the immune microenvironment and tryptophan metabolism in breast cancer, and it predicts poor prognosis in breast cancer, which suggests that TDO2 might be a promising novel immunotherapy target for breast cancer. Additionally, we established the concept that tryptophan-catabolizing enzymes (IDO1, IDO2, TDO2, and KYNU) may function through co-regulating the immunological microenvironment, and thus immunotherapy targeting IDO1 alone might be insufficient.

之前的大量研究都集中在吲哚胺 2,3-双加氧酶 1 (IDO1) 在癌症免疫中的作用。然而，癌症免疫治疗中针对色氨酸 2,3-双加氧酶 (TDO2) 的另一种方法在很大程度上被忽视了。特别是，TDO2 在乳腺癌中的具体作用仍不清楚。在本研究中，我们利用大规模转录组数据系统地探索和验证了 TDO2 在乳腺癌中的表达和预后价值。我们观察到与邻近正常组织相比，许多类型的癌症组织中 TDO2 过度表达。TDO2 过表达被发现与乳腺癌的恶性程度和肿瘤分级呈正相关。TDO2 在雌激素阴性乳腺癌和三阴性乳腺癌中表达较高，并且与乳腺癌患者较差的预后相关。TDO2 表达与免疫浸润和色氨酸代谢相关基因（IDO1 和犬尿氨酸酶 [KYNU]）相关。因此，我们的结果表明，TDO2在调节乳腺癌的免疫微环境和色氨酸代谢中发挥着关键作用，并预测乳腺癌的不良预后，这表明TDO2可能是乳腺癌的一个有前途的新型免疫治疗靶点。此外，我们建立了这样的概念：色氨酸分解酶（IDO1、IDO2、TDO2 和 KYNU）可能通过共同调节免疫微环境发挥作用，因此单独针对 IDO1 的免疫疗法可能是不够的。