Li Jianpeng, Jiang Yunzhong, Ma Minghai, Wang Lu, Jing Minxuan, Yang Zezhong, Zhang Mengzhao, Chen Ke, Fan Jinhai
Department of Urology, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
Department of Vascular Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi Province, China.
J Transl Med. 2025 Jan 30;23(1):135. doi: 10.1186/s12967-025-06138-6.
The progression of bladder cancer (BC) from non-muscle-invasive bladder cancer (NMIBC) to muscle-invasive bladder cancer (MIBC) significantly increases disease severity. Although the tumor microenvironment (TME) plays a pivotal role in this process, the heterogeneity of tumor cells and TME components remains underexplored.
We characterized the transcriptomes of single cells from 11 BC samples, including 4 NMIBC, 4 MIBC, and 3 adjacent normal tissues. Bulk RNA-seq data were used to validate the clinical features of characteristic cells, and protein levels of these cells were further confirmed through immunohistochemistry (IHC) and multiplex immunofluorescence.
Bladder cancer progression was associated with distinct transcriptomic features in the TME. Tumor cells in MIBC displayed enhanced glycolytic activity and downregulation of chemokines and MHC-II molecules, reducing immune cell recruitment and facilitating immune evasion. This highlights glycolysis as a potential therapeutic target for disrupting tumor progression. We identified a T cell exhaustion pathway from naive CD8 + T cells (CD8 + TCF7) to terminally exhausted CD8 + STMN1 cells, with progressively declining immune surveillance. Targeting intermediate exhaustion states may restore T cell function and improve anti-tumor immunity. Macrophages polarized toward a pro-tumorigenic phenotype, while VEGFA + mast cells promoted angiogenesis in early-stage BC, suggesting their role as potential targets for therapeutic intervention in NMIBC. Furthermore, conventional dendritic cells (DCs) transformed into LAMP3 + DCs, contributing to an immunosuppressive microenvironment and enabling immune evasion.
This study reveals dynamic changes in the TME during BC progression, including enhanced glycolysis, T cell exhaustion, and immune cell remodeling, which contribute to immune evasion and tumor progression. These findings identify critical pathways and cell populations as potential therapeutic targets, offering new strategies to improve treatment outcomes in BC patients.
膀胱癌（BC）从非肌层浸润性膀胱癌（NMIBC）进展为肌层浸润性膀胱癌（MIBC）会显著增加疾病的严重程度。尽管肿瘤微环境（TME）在此过程中起关键作用，但肿瘤细胞和TME成分的异质性仍未得到充分探索。
我们对11例BC样本中的单细胞转录组进行了表征，包括4例NMIBC、4例MIBC和3例相邻正常组织。批量RNA测序数据用于验证特征细胞的临床特征，并通过免疫组织化学（IHC）和多重免疫荧光进一步确认这些细胞的蛋白质水平。
膀胱癌进展与TME中不同的转录组特征相关。MIBC中的肿瘤细胞表现出增强的糖酵解活性以及趋化因子和MHC-II分子的下调，减少了免疫细胞募集并促进了免疫逃逸。这突出了糖酵解作为破坏肿瘤进展的潜在治疗靶点。我们确定了一条从初始CD8 + T细胞（CD8 + TCF7）到终末耗竭CD8 + STMN1细胞的T细胞耗竭途径，免疫监视逐渐下降。靶向中间耗竭状态可能恢复T细胞功能并改善抗肿瘤免疫力。巨噬细胞向促肿瘤表型极化，而VEGFA + 肥大细胞在早期BC中促进血管生成，表明它们作为NMIBC治疗干预潜在靶点的作用。此外，传统树突状细胞（DC）转变为LAMP3 + DC，促成免疫抑制微环境并实现免疫逃逸。
本研究揭示了BC进展过程中TME的动态变化，包括糖酵解增强、T细胞耗竭和免疫细胞重塑，这些变化有助于免疫逃逸和肿瘤进展。这些发现确定了关键途径和细胞群体作为潜在治疗靶点，为改善BC患者的治疗结果提供了新策略。
