Finan Jennifer M, Guo Yifei, Goodyear Shaun M, Brody Jonathan R
Department of Surgery, Oregon Health & Science University, Portland, OR.
Knight Cancer Institute, Oregon Health & Science University, Portland, OR.
JCO Oncol Adv. 2024 Dec 18;1:e2400050. doi: 10.1200/OA-24-00050. eCollection 2024.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths with a 5-year survival rate of 13%. Surgical resection remains the only curative option as systemic therapies offer limited benefit. Poor response to chemotherapy and immunotherapy is due, in part, to the dense stroma and heterogeneous tumor microenvironment (TME). Opportunities to target the PDAC stroma may increase the effectiveness of existing or novel therapies. Current strategies targeting the stromal compartment within the PDAC TME primarily focus on degrading extracellular matrix or inhibiting stromal cell activity, angiogenesis, or hypoxic responses. In addition, extensive work has attempted to use immune targeting strategies to improve clinical outcomes. Preclinically, these strategies show promise, especially with the ability to alter the tumor ecosystem; however, when translated to the clinic, most of these trials have failed to improve overall patient outcomes. In this review, we catalog the heterogenous elements of the TME and discuss the potential of combination therapies that target the heterogeneity observed in the TME between patients and how molecular stratification could improve responses to targeted and combination therapies.
胰腺导管腺癌（PDAC）是癌症相关死亡的第三大主要原因，5年生存率为13%。手术切除仍然是唯一的治愈选择，因为全身治疗的益处有限。对化疗和免疫治疗反应不佳部分归因于致密的间质和异质性肿瘤微环境（TME）。靶向PDAC间质的机会可能会提高现有或新型疗法的有效性。目前针对PDAC TME中间质区室的策略主要集中在降解细胞外基质或抑制间质细胞活性、血管生成或缺氧反应。此外，大量工作试图使用免疫靶向策略来改善临床结果。在临床前，这些策略显示出前景，特别是具有改变肿瘤生态系统的能力；然而，当转化到临床时，这些试验中的大多数未能改善患者的总体预后。在这篇综述中，我们梳理了TME的异质成分，并讨论了联合疗法的潜力，这些联合疗法针对患者之间TME中观察到的异质性，以及分子分层如何改善对靶向治疗和联合治疗的反应。
