Cammarota Antonella, Balsano Rita, Pressiani Tiziana, Bozzarelli Silvia, Rimassa Lorenza, Lleo Ana
Hepatobiliary Immunopathology Laboratory, IRCCS Humanitas Research Hospital, 20089 Rozzano, Italy.
Department of Biomedical Sciences, Humanitas University, 20090 Pieve Emanuele, Italy.
Cancers (Basel). 2025 Jan 15;17(2):272. doi: 10.3390/cancers17020272.
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, rearrangements or fusions (7-15%) and mutations (10-20%) are common in iCCA, while amplifications/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（CCA）约占所有胃肠道癌症的3%，是一种高度异质性且侵袭性强的恶性肿瘤，起源于胆管树的上皮细胞。CCA按解剖位置分为肝内胆管癌（iCCA）、肝外胆管癌（eCCA）、胆囊癌（GBC）和壶腹癌。尽管被认为是一种罕见肿瘤，但全球范围内CCA的发病率呈上升趋势，尤其是由于iCCA诊断率的提高。基因组和免疫谱分析研究揭示了CCA内部存在显著的异质性，导致在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iCCA中。其中，重排或融合（7%-15%）以及 突变（10%-20%）在iCCA中较为常见，而 扩增/过表达在eCCA和GBC中更为频繁。CCA的肿瘤免疫微环境（TIME）在疾病的发病机制和进展中发挥着积极作用，营造了一个以免疫抑制细胞群为主导的复杂且可塑性强的环境。其中，癌症相关成纤维细胞（CAF）是TIME的关键组成部分，因其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免疫原性较差的环境，从而与较差的生存率相关。对CCA肿瘤生物学的深入了解推动了新型治疗方法的发展。顺铂和吉西他滨与免疫检查点抑制剂（ICI）的联合疗法已取代了长达十年的标准双联化疗，成为晚期CCA患者的新护理标准。然而，生存率的提高仍然有限，这促使人们研究更有效的方法来靶向CCA的TIME。随着CCA免疫逃逸的关键机制被揭示，新型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、血管生成以及导致免疫逃逸的肿瘤特异性抗原的策略。此外,ICI在晚期CCA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CCA的免疫生物学，并探讨了这些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。
