肿瘤细胞治疗研究
英文原题：Elevated interstitial fluid pressure promotes spheroid growth and reduces CAR-T therapeutic efficacy in solid tumors.
胰腺导管腺癌（PDAC）是最致命的实体瘤之一，其特征为侵袭性进展、致密的肿瘤微环境（TME）以及对常规治疗的耐药。
胰腺导管腺癌（PDAC）是致死率最高的实体瘤之一，具有进展迅速、肿瘤微环境（TME）致密及对常规治疗耐药等特点。高间质液压（IFP）可能妨碍药物渗透和免疫细胞浸润，是有效治疗的障碍之一。本研究构建了一种创新的PDAC三维微流控芯片模型，可在细胞腔室中施加IFP以模拟TME，并评估针对肿瘤细胞所表达EGFR工程化的CAR-T细胞疗效。高IFP与肿瘤球生长增加、半胱天冬酶活化减少及肌动蛋白重塑降低相关，提示肿瘤耐受性增强。在正常压力条件下，CAR-T细胞可在二维及三维共培养模型中有效靶向并清除肿瘤细胞；但在高IFP下，CAR-T介导的细胞毒作用受损，说明实体瘤CAR-T疗效偏低可能部分源于IFP。这些结果凸显机械微环境对当前免疫疗法疗效的限制作用。纳入IFP因素的模型可作为更真实的实体瘤抗肿瘤疗法临床前测试平台。 **意义声明：**本研究建立了一种纳入实体瘤关键力学因素——间质液压（IFP）的创新型三维胰腺肿瘤芯片模型。利用该平台，研究发现IFP促进肿瘤增殖，同时削弱免疫疗法疗效。这表明机械压力在限制实体瘤免疫细胞功能方面具有重要作用。该模型可用于研究抗肿瘤疗法的疗效，并支持开发克服机械性耐受、增强实体瘤（如胰腺癌）治疗效果的策略。
Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest solid tumors and is characterized by aggressive progression, a dense tumor microenvironment (TME), and resistance to conventional therapies. Among the barriers to effective treatments, the presence of elevated interstitial fluid pressure (IFP) may be important for drug penetration and immune cell infiltration. In this work, we present an innovative 3D microfluidic PDAC-on-a-chip that allows the application of IFP in a cell chamber to simulate the TME and evaluate the therapeutic efficacy of CAR-T cells engineered against the receptor EGFR expressed in tumor cells. Elevated IFP was associated with increased tumor spheroid growth, reduced caspase activation and decreased actin remodeling, indicating enhanced tumor resistance. CAR-T cells effectively targeted and eliminated tumor cells in 2D and 3D coculture models under normal pressure conditions. However, under high IFP, CAR-T-mediated cytotoxicity was impaired, indicating that some of the low efficacy of CAR-T cell therapy against solid tumors might be derived from IFP. These results highlight the importance of the mechanoenvironment in limiting the efficacy of current immunotherapies. Our model, which incorporates an IFP component, serves as a realistic preclinical platform for testing antitumor therapies in solid tumors. Statement of Significance In this work, we present an innovative 3D pancreatic tumor-on-a-chip model that incorporates interstitial fluid pressure (IFP), which is a key mechanical component of solid tumors. Using this platform, we discovered that IFP enhances tumor proliferation whilst diminishing immunotherapy efficacy. This indicates the important role of mechanical pressure in limiting immune cell function in solid tumors. Our model is a valuable preclinical platform for investigating the efficacy of anti-tumor therapies and supports the development of strategies to overcome mechanical resistance and enhance therapy efficacy in solid tumors, such as pancreatic cancer.
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