Ramesh Remya P G, Yasmin Hadida, Ponnachan Pretty, Al-Ramadi Basel, Kishore Uday, Joseph Ann Mary
Department of Veterinary Medicine, UAE University, Al Ain, United Arab Emirates.
Immunology and Cell Biology Laboratory, Department of Zoology, Cooch Behar Panchanan Barma University, Cooch Behar, West Bengal, India.
Front Immunol. 2025 Mar 31;16:1573522. doi: 10.3389/fimmu.2025.1573522. eCollection 2025.
Pancreatic cancer is an aggressive tumor with high metastatic potential which leads to decreased survival rate and resistance to chemotherapy and immunotherapy. Nearly 90% of pancreatic cancer comprises pancreatic ductal adenocarcinoma (PDAC). About 80% of diagnoses takes place at the advanced metastatic stage when it is unresectable, which renders chemotherapy regimens ineffective. There is also a dearth of specific biomarkers for early-stage detection. Advances in next generation sequencing and single cell profiling have identified molecular alterations and signatures that play a role in PDAC progression and subtype plasticity. Most chemotherapy regimens have shown only modest survival benefits, and therefore, translational approaches for immunotherapies and combination therapies are urgently required. In this review, we have examined the immunosuppressive and dense stromal network of tumor immune microenvironment with various metabolic and transcriptional changes that underlie the pro-tumorigenic properties in PDAC in terms of phenotypic heterogeneity, plasticity and subtype co-existence. Moreover, the stromal heterogeneity as well as genetic and epigenetic changes that impact PDAC development is discussed. We also review the PDAC interaction with sequestered cellular and humoral components present in the tumor immune microenvironment that modify the outcome of chemotherapy and radiation therapy. Finally, we discuss different therapeutic interventions targeting the tumor immune microenvironment aimed at better prognosis and improved survival in PDAC.
胰腺癌是一种具有高转移潜能的侵袭性肿瘤，会导致生存率降低以及对化疗和免疫疗法产生耐药性。近90%的胰腺癌为胰腺导管腺癌（PDAC）。约80%的病例在无法切除的晚期转移阶段被诊断出来，这使得化疗方案无效。此外，早期检测的特异性生物标志物也很缺乏。新一代测序和单细胞分析技术的进展已经确定了在PDAC进展和亚型可塑性中起作用的分子改变和特征。大多数化疗方案仅显示出适度的生存获益，因此，迫切需要免疫疗法和联合疗法的转化方法。在这篇综述中，我们从表型异质性、可塑性和亚型共存的角度，研究了肿瘤免疫微环境的免疫抑制和致密基质网络以及各种代谢和转录变化，这些变化构成了PDAC促肿瘤特性的基础。此外，还讨论了影响PDAC发展的基质异质性以及基因和表观遗传变化。我们还回顾了PDAC与肿瘤免疫微环境中隔离的细胞和体液成分的相互作用，这些成分会改变化疗和放疗的结果。最后，我们讨论了针对肿瘤免疫微环境的不同治疗干预措施，旨在改善PDAC的预后和提高生存率。
