About 70% of bladder cancers (BCs) are diagnosed as non-muscle-invasive BCs (NMIBCs), while the remaining are muscle-invasive BCs (MIBCs). The European Association of Urology (EAU) guidelines stratify NMIBCs into low, intermediate, and high risk for treatment options. Low-risk NMIBCs undergo only the transurethral resection of the bladder (TURB), whereas for intermediate-risk and high-risk NMIBCs, the transurethral resection of the bladder (TURB) with or without Bacillus Calmette-Guérin (BCG) immune or chemotherapy is the standard treatment. A minority of NMIBCs show unfavorable prognosis. High-risk NMIBCs have a high rate of disease recurrence and/or progression to muscle-invasive tumor and BCG treatment failure. The heterogeneous nature of NMIBCs poses challenges for clinical decision-making. In 2020, the EAU made some changes to NMIBCs BCG failure definitions and treatment options, highlighting the need for reliable molecular markers for improving the predictive accuracy of currently available risk tables. Nowadays, next-generation sequencing (NGS) has revolutionized the study of cancer biology, providing diagnostic, prognostic, and therapy response biomarkers in support of precision medicine. Integration of NGS with other cutting-edge technologies might help to decipher also bladder tumor surrounding aspects such as immune system, stromal component, microbiome, and urobiome; altogether, this might impact the clinical outcomes of NMBICs especially in the BCG responsiveness. This review focuses on NMIBCs with unfavorable prognoses, providing molecular prognostic factors from tumor immune and stromal cells, and the perspective of urobiome and microbiome profiling on therapy response. We provide information on the cornerstone of immunotherapy and new promising bladder-preserving treatments and ongoing clinical trials for BCG–unresponsive NMIBCs.

大约70％的膀胱癌（BCs）被诊断为非肌肉浸润性BC（NMIBC），而其余的则是肌肉浸润性BC（MIBC）。欧洲泌尿外科协会（EAU）指南将NMIBC分为治疗选择的低，中和高风险。低危NMIBC仅经过膀胱尿道切除术（TURB），而中危和高危NMIBC仅需进行尿道膀胱切除术（TURB）有无卡尔梅特芽孢杆菌（BCG）免疫或化学疗法是标准治疗方法。少数NMIBC的预后不良。高风险的NMIBC具有很高的疾病复发率和/或进展为肌肉浸润性肿瘤和BCG治疗失败。NMIBC的异质性为临床决策提出了挑战。2020年，EAU对NMIBC的BCG失败定义和治疗方案进行了一些更改，强调了对可靠的分子标记物的需求，以提高当前可用风险表的预测准确性。如今，下一代测序（NGS）彻底改变了癌症生物学研究，提供了诊断，预后和治疗反应生物标志物，以支持精密医学。NGS与其他前沿技术的集成可能有助于解读膀胱肿瘤周围的各个方面，例如免疫系统，基质成分，微生物组和尿液组；总体而言，这可能会影响NMBIC的临床结果，尤其是在BCG反应性方面。这篇综述聚焦于预后不良的NMIBCs，提供了来自肿瘤免疫和基质细胞的分子预后因素，以及尿嘧啶和微生物组对治疗反应的影响。我们提供有关BCG无反应的NMIBC的免疫疗法和有前途的膀胱保存疗法的基础知识以及正在进行的临床试验的信息。这篇综述聚焦于预后不良的NMIBCs，提供了来自肿瘤免疫和基质细胞的分子预后因素，以及尿嘧啶和微生物组对治疗反应的影响。我们提供有关BCG无反应的NMIBC的免疫疗法和有前途的膀胱保存疗法的基础知识以及正在进行的临床试验的信息。这篇综述聚焦于预后不良的NMIBCs，提供了来自肿瘤免疫和基质细胞的分子预后因素，以及尿嘧啶和微生物组对治疗反应的影响。我们提供有关BCG无反应的NMIBC的免疫疗法和有前途的膀胱保存疗法的基础知识以及正在进行的临床试验的信息。