基于三维血管化肿瘤模型评估及优化肝癌介入治疗和免疫治疗

  原发性肝癌是我国第四大常见的恶性肿瘤，由于高侵袭率和致死率仍然面临严峻的健康挑战。经动脉化疗栓塞（TACE）作为不可手术切除肝癌的一线疗法，临床上主要通过介入微创手术使用载药栓塞剂阻断肿瘤供血动脉并同时疏送化疗药物至肿瘤部位。然而，TACE 疗法疗效并不理想，仍存在误栓风险和栓塞不完全易导致高复发率等痛点。目前，TACE 疗法与其他疗法（如局部热疗、免疫疗法等）结合成为了肝癌治疗研究的主要方向，但均缺乏有效的评估模型而强烈依赖于临床实验，导致研究进展缓慢。本研究的主要目的是构建适用于评估富血供肝癌疗法的三维血管化肿瘤模型，深入评估并探究TACE 疗法中栓塞化疗的关键性难点，并在此基础上开发精准栓塞疗法减少误栓风险以及优化免疫疗法巩固治疗疗效，为 TACE治疗提供更加有效的辅助治疗方案。

    本研究中我们创新性地提出了一种三维血管化肿瘤模型，该模型利用脱细胞肝脏支架植入肿瘤细胞，保持了肝静脉、门静脉和肝动脉等多套血管的畅通，并在此基础上首次实现多种疗法的评估。我们首先利用该模型对TACE疗法进行评估，通过门静脉注射药物洗脱微球模拟栓塞化疗，并通过肝静脉输送氧气和养分保证肿瘤模型的细胞活性，对栓塞分布、药物扩散深度以及细胞对药物扩散和营养供应平衡的反应进行评估与量化，发现临床用球形载药栓塞微球易漂移产生误栓，且栓塞血管外基质药物有效递送深度受制于肿瘤周围的残留血供，极大地影响了栓塞化疗疗效。基于此，我们提出了经导管精准光热栓塞（EPPE）辅助疗法，首次利用介入微导管将光纤精准导入供血血管入口处，通过光热效应诱导局部栓塞，达到完全阻断整个肿瘤血液供应的目的，并在血管化肿瘤模型和大鼠肝脏模型中进行了验证。此外，肝癌免疫疗法有望解决TACE疗法中残余血供的问题，但仍缺乏特异性靶点。我们提出了新抗原相关的过继性毒性T淋巴细胞（CTL）免疫疗法，成功筛选出了6条具有高免疫原性肝癌新抗原，建立了新抗原修饰的HepG2三维血管化肿瘤模型，并对模型中新抗原修饰的HepG2细胞与特异性T细胞的免疫反应进行了验证。

    综上所述，我们构建了三维血管化肝脏肿瘤模型对TACE疗法，EPPE疗法和CTL免疫疗法等三种肝癌疗法进行了有效的评估。其中EPPE疗法作为一种全新的介入热疗方法，不仅解决了光热穿透深度的难题，而且避免了传统TACE疗法误栓风险；同时CTL免疫疗法成功筛选出了多个特异性靶点，有望用于开发个性化肝癌疫苗。这两种新型疗法有望与TACE疗法结合，提供新的治疗策略以提高肝癌的治疗疗效。

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