神经内分泌膀胱癌（NEBC）提出了巨大的临床挑战，并引起了人们对探索免疫疗法作为可行的治疗选择的浓厚兴趣。然而，全面的免疫基因组景观尚未得到彻底研究。利用自然 NEBC 病例的长期队列，我们​​采用了一种多模式方法，整合了基因组 (n = 19)、转录组 (n = 3)、单细胞 RNA 测序 ( n = 1) 和免疫组织化学分析 (n = 34)，以仔细表征原发性 NEBC 肿瘤的免疫原性和免疫类型。回顾性检索和分析临床、病理、医学影像和治疗信息。我们的研究表明，尽管存在相当大的突变负担，NEBC 通常是免疫不活跃的，如“免疫排除”或“免疫沙漠”微环境所表现的那样。有趣的是，混合 NEBC 与并发尿路上皮膀胱癌 (UBC) 组织学的一个子集显示出具有预后相关性的“免疫浸润”表型。与 UBC 相比，NEBC 病变的特点是细胞成分更致密，瘤周细胞外基质增多，这可能共同阻碍淋巴浸润。因此，单药免疫检查点抑制剂对 NEBC 的疗效有限，而药物免疫刺激联合化疗可产生更有利的反应。这些来自基因组分析和免疫表型分析的新见解为 NEBC 患者的合理免疫治疗干预铺平了道路。最终降低这种致命疾病的死亡率的潜力。

Neuroendocrine bladder cancer (NEBC) poses a formidable clinical challenge and attracts keen interests to explore immunotherapy as a viable treatment option. However, a comprehensive immunogenomic landscape has yet to be thoroughly investigated.Leveraging a long-term cohort of natural NEBC cases, we employed a multimodal approach integrating genomic (n = 19), transcriptomic (n = 3), single-cell RNA sequencing (n = 1), and immunohistochemical analyses (n = 34) to meticulously characterize the immunogenicity and immunotypes of primary NEBC tumors. Clinical, pathological, medical imaging, and treatment information was retrospectively retrieved and analyzed.Our study unveiled that despite a considerable mutational burden, NEBC was typically immunologically inactive, as manifested by 'immune-excluded' or 'immune-desert' microenvironment. Interestingly, a subset of mixed NEBC with concurrent urothelial bladder cancer (UBC) histology displayed an 'immune-infiltrated' phenotype with prognostic relevance. When compared to UBC, NEBC lesions were distinguished by a denser cellular composition and augmented peritumoral extracellular matrix, which might collectively impede lymphatic infiltration. As a result, single-agent immune checkpoint inhibitors demonstrated limited efficacy against NEBC, while pharmacologic immunostimulation with combination chemotherapy conferred a more favorable response.These new insights derived from genomic profiling and immune phenotyping pave the way for rational immunotherapeutic interventions in NEBC patients, with the potential to ultimately reduce mortality from this otherwise fatal disease.