背景：ACER2是一个重要的基因，调节癌细胞的生长和迁移，然而ACER2在肿瘤微环境（TME）中的免疫学角色鲜有报道。因此，我们研究ACER2在膀胱癌（BLCA）中的潜在表现。方法：我们首先基于从癌症基因组图谱（TCGA）和我们的湘雅队列收集的数据，比较了BLCA和正常尿路上皮组织中ACER2的表达。随后，我们系统地探索了ACER2与免疫调节剂、抗癌免疫周期、肿瘤浸润免疫细胞、免疫检查点和T细胞注射性评分（TIS）之间的相关性，进一步确认其在BLCA TME中的免疫学角色。此外，我们进行了ROC分析，以说明ACER2在预测BLCA分子亚型方面的准确性，并探索了对几种癌症相关治疗的反应。最后，我们在免疫治疗队列和湘雅队列中验证了结果，以确保研究的稳定性。结果：与正常尿路上皮相比，ACER2在几种细胞系和BLCA肿瘤组织中显著过表达。ACER2可导致非炎性BLCA TME的形成，其与免疫调节剂、抗癌免疫周期、肿瘤浸润免疫细胞、免疫检查点和TIS的负相关支持这一结论。此外，ACER2高表达的BLCA患者倾向于腺管亚型，这些亚型表现出对新辅助化疗、化疗和放疗的不敏感，但对免疫治疗没有不敏感。IMvigor210和湘雅队列的结果一致。结论：ACER2可以准确预测BLCA的TME和临床结果，未来可以作为精准治疗的有前途的靶点。版权所有©2023年刘、程、祁、肖、周、邓和戴。

Background: ACER2 is a critical gene regulating cancer cell growth and migration, whereas the immunological role of ACER2 in the tumor microenvironment (TME) is scarcely reported. Thus, we lucubrate the potential performance of ACER2 in bladder cancer (BLCA). Methods: We initially compared ACER2 expressions in BLCA with normal urothelium tissues based on data gathered from the Cancer Genome Atlas (TCGA) and our Xiangya cohort. Subsequently, we systematically explored correlations between ACER2 with immunomodulators, anti-cancer immune cycles, tumor-infiltrating immune cells, immune checkpoints and the T-cell inflamed score (TIS) to further confirm its immunological role in BLCA TME. In addition, we performed ROC analysis to illustrate the accuracy of ACER2 in predicting BLCA molecular subtypes and explored the response to several cancer-related treatments. Finally, we validated results in an immunotherapy cohort and Xiangya cohort to ensure the stability of our study. Results: Compared with normal urinary epithelium, ACER2 was significantly overexpressed in several cell lines and the tumor tissue of BLCA. ACER2 can contribute to the formation of non-inflamed BLCA TME supported by its negative correlations with immunomodulators, anti-cancer immune cycles, tumor-infiltrating immune cells, immune checkpoints and the TIS. Moreover, BLCA patients with high ACER2 expression were inclined to the luminal subtype, which were characterized by insensitivity to neoadjuvant chemotherapy, chemotherapy and radiotherapy but not to immunotherapy. Results in the IMvigor210 and Xiangya cohort were consistent. Conclusion: ACER2 could accurately predict the TME and clinical outcomes for BLCA. It would be served as a promising target for precision treatment in the future.Copyright © 2023 Liu, Cheng, Qi, Xiao, Zhou, Deng and Dai.