肿瘤细胞治疗研究
英文原题：Advances, challenges, and innovative strategies of CAR-T cell therapy in pancreatic cancer.
胰腺癌仍然是全球最致命的恶性肿瘤之一，其中胰腺导管腺癌（PDAC）占大多数病例，且预后持续不佳。
胰腺癌仍然是全球范围内最致命的恶性肿瘤之一，其中胰腺导管腺癌（PDAC）占大多数病例，且预后持续较差。尽管CAR-T（CAR-T）细胞疗法在血液系统恶性肿瘤中取得了显著成功，但其在胰腺癌中的治疗疗效仍然有限。本综述总结了CAR-T细胞疗法治疗胰腺癌的最新进展，重点关注具有代表性的肿瘤相关靶点，包括间皮素（MSLN）、紧密连接蛋白18.2（CLDN18.2）、前列腺干细胞抗原（PSCA）、CD155、CD276、生长停滞特异性蛋白6（GAS6）和磷脂酰肌醇蛋白聚糖-1（GPC1），同时着重介绍新兴的下一代CAR-T工程化策略，包括基于纳米抗体的抗原识别、细胞因子装甲CAR-T细胞、同种异体CAR-NKT平台、双靶点和逻辑门控CAR系统以及创新性递送方法。目前的临床前和早期临床证据表明，若干靶点，尤其是MSLN和CLDN18.2，显示出有前景的抗肿瘤活性；然而，持久的临床缓解仍然难以实现。主要障碍包括致密的促纤维增生性基质、高度免疫抑制的肿瘤微环境（TME）、抗原异质性、抗原丢失、CAR-T持久性和扩增有限、T细胞耗竭以及靶向非肿瘤毒性。为克服这些障碍，新兴策略集中于重塑TME、工程化装甲或双靶点CAR-T细胞、开发逻辑门控CAR系统、改善CAR-T持久性，以及通过纳米材料、溶瘤病毒、原位CAR-T生成、替代性免疫细胞载体和局部区域给药来优化递送方法。总体而言，胰腺癌的 CAR-T 治疗正从临床前探索向临床转化推进。未来的成功可能取决于合理的靶点选择、多维度的 TME 调控、先进的 CAR 工程改造、精准递送以及生物标志物指导的患者分层。
Pancreatic cancer remains one of the most lethal malignancies worldwide, with pancreatic ductal adenocarcinoma (PDAC) accounting for the majority of cases and exhibiting a persistently poor prognosis. Although chimeric antigen receptor T (CAR-T) cell therapy has achieved remarkable success in hematological malignancies, its therapeutic efficacy in pancreatic cancer remains limited. This review summarizes recent advances in CAR-T cell therapy for pancreatic cancer, with a focus on representative tumor-associated targets, including mesothelin (MSLN), claudin 18.2 (CLDN18.2), prostate stem cell antigen (PSCA), CD155, CD276, growth arrest-specific protein 6 (GAS6), and glypican-1 (GPC1), while also highlighting emerging next-generation CAR-T engineering strategies, including nanobody-based antigen recognition, cytokine-armored CAR-T cells, allogeneic CAR-NKT platforms, dual-target and logic-gated CAR systems, and innovative delivery approaches. Current preclinical and early clinical evidence suggests that several targets, particularly MSLN and CLDN18.2, show promising antitumor activity; however, durable clinical responses remain difficult to achieve. The major barriers include the dense desmoplastic stroma, highly immunosuppressive tumor microenvironment (TME), antigen heterogeneity, antigen loss, limited CAR-T persistence and expansion, T-cell exhaustion, and on-target, off-tumor toxicity. To overcome these obstacles, emerging strategies have focused on remodeling the TME, engineering armored or dual-target CAR-T cells, developing logic-gated CAR systems, improving CAR-T persistence, and optimizing delivery approaches through nanomaterials, oncolytic viruses, in situ CAR-T generation, alternative immune-cell carriers, and locoregional administration. Overall, CAR-T therapy for pancreatic cancer is progressing from preclinical exploration toward clinical translation. Future success will likely depend on rational target selection, multi-dimensional TME modulation, advanced CAR engineering, precision delivery, and biomarker-guided patient stratification.
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