Cholangiocarcinoma (CCA) represents approximately 3% of all gastrointestinal cancers and is a highly heterogeneous and aggressive malignancy originating from the epithelial cells of the biliary tree. CCA is classified by anatomical location into intrahepatic (iCCA), extrahepatic (eCCA), gallbladder cancer (GBC), and ampullary cancers. Although considered a rare tumor, CCA incidence has risen globally, particularly due to the increased diagnosis of iCCA. Genomic and immune profiling studies have revealed significant heterogeneity within CCA, leading to the identification of molecular subtypes and actionable genetic alterations in 40–60% of cases, particularly in iCCA. Among these,FGFR2rearrangements or fusions (7–15%) andIDH1mutations (10–20%) are common in iCCA, whileHER2amplifications/overexpression are more frequent in eCCA and GBC. The tumor-immune microenvironment (TIME) of CCAs plays an active role in the pathogenesis and progression of the disease, creating a complex and plastic environment dominated by immune-suppressive populations. Among these, cancer-associated fibroblasts (CAFs) are a key component of the TIME and are associated with worse survival due to their role in maintaining a poorly immunogenic landscape through the deposition of stiff extracellular matrix and release of pro-tumor soluble factors. Improved understanding of CCA tumor biology has driven the development of novel treatments. Combination therapies of cisplatin and gemcitabine with immune checkpoint inhibitors (ICIs) have replaced the decade-long standard doublet chemotherapy, becoming the new standard of care in patients with advanced CCA. However, the survival improvements remain modest prompting research into more effective ways to target the TIME of CCAs. As key mechanisms of immune evasion in CCA are uncovered, novel immune molecules emerge as potential therapeutic targets. Current studies are exploring strategies targeting multiple immune checkpoints, angiogenesis, and tumor-specific antigens that contribute to immune escape. Additionally, the success of ICIs in advanced CCA has led to interest in their application in earlier stages of the disease, such as in adjuvant and neoadjuvant settings. This review offers a comprehensive overview of the immune biology of CCAs and examines how this knowledge has guided clinical drug development, with a focus on both approved and emergent treatment strategies.
胆管癌约占所有胃肠道癌症的3%，是一种起源于胆道上皮细胞的高度异质性和侵袭性的恶性肿瘤。根据解剖位置，胆管癌可分为肝内胆管癌、肝外胆管癌、胆囊癌和壶腹癌。尽管被认为是一种罕见肿瘤，但胆管癌的发病率在全球范围内呈上升趋势，尤其是由于肝内胆管癌诊断率的提高。基因组和免疫谱分析研究揭示了胆管癌内部显著的异质性，从而在40-60%的病例中识别出分子亚型和可操作的基因改变，特别是在肝内胆管癌中。其中，FGFR2重排或融合（7-15%）和IDH1突变（10-20%）在肝内胆管癌中较为常见，而HER2扩增/过表达在肝外胆管癌和胆囊癌中更为常见。胆管癌的肿瘤免疫微环境在疾病的发生和发展中起着积极作用，形成了一个以免疫抑制群体为主的复杂且可塑的环境。其中，癌症相关成纤维细胞是肿瘤免疫微环境的关键组成部分，并通过沉积坚硬的细胞外基质和释放促肿瘤可溶性因子来维持低免疫原性环境，与较差的生存率相关。对胆管癌肿瘤生物学的深入理解推动了新型治疗方法的发展。顺铂和吉西他滨联合免疫检查点抑制剂的治疗方案已取代了长达十年的标准双药化疗，成为晚期胆管癌患者的新标准治疗。然而，生存期的改善仍然有限，这促使人们研究更有效的方法来靶向胆管癌的肿瘤免疫微环境。随着胆管癌免疫逃逸的关键机制被揭示，新的免疫分子成为潜在的治疗靶点。目前的研究正在探索针对多种免疫检查点、血管生成和肿瘤特异性抗原的策略，这些因素均有助于免疫逃逸。此外，免疫检查点抑制剂在晚期胆管癌中的成功应用，引发了人们对其在疾病早期阶段（如辅助和新辅助治疗）应用的兴趣。本综述全面概述了胆管癌的免疫生物学，并探讨了这一知识如何指导临床药物开发，重点关注已批准和新兴的治疗策略。
The Immune–Genomics of Cholangiocarcinoma: A Biological Footprint to Develop Novel Immunotherapies
肿瘤(癌症)患者之家