肿瘤细胞治疗研究
英文原题：Innovative gene engineering strategies to address tumor antigen escape in cell therapy.
这些进展标志着向可适应、即用型、生物标志物指导的平台转变，这些平台旨在跟上肿瘤演化并实现抗逃逸免疫。
肿瘤抗原逃逸限制了抗原特异性免疫疗法的持久性，尤其是基于嵌合抗原受体（CAR）的治疗。恶性细胞通过六种途径逃避检测：抗原突变或可变剪接、抗原加工受损、谱系转换、膜再分布、trogocytic表位掩蔽以及自体制造过程中的CAR诱导屏蔽。这些策略最初在血液系统癌症中被发现，如今在实体瘤中日益显现，其中异质性和免疫抑制加剧了逃逸。新兴的对策拓宽或恢复了抗原识别：多特异性模式（双特异性/串联CAR、双特异性衔接器、适配器CAR）、逻辑门控synNotch回路、抗原上调mRNA疫苗和表观遗传药物，以及非常规效应细胞如恒定自然杀伤T（iNKT）、γδ T和黏膜相关恒定T（MAIT）细胞。总体而言，这些进展标志着向可适应、现货型、生物标志物引导平台的转变，旨在跟上肿瘤进化并实现抗逃逸免疫。
Tumor antigen escape limits the durability of antigen-specific immunotherapies, particularly chimeric antigen receptor (CAR)-based treatments. Malignant cells evade detection through six routes: antigen mutation or alternative splicing, impaired antigen processing, lineage switching, membrane redistribution, trogocytic epitope masking, and CAR-induced shielding during autologous manufacture. First noted in blood cancers, these tactics increasingly appear in solid tumors, where heterogeneity and immune suppression exacerbate escape. Emerging countermeasures broaden or restore antigen recognition: multi-specific modalities (dual/tandem CARs, bispecific engagers, adaptor CARs), logic-gated synNotch circuits, antigen-upregulating mRNA vaccines and epigenetic drugs, and non-conventional effectors such as invariant natural killer T (iNKT), gamma delta T (γδ T), and mucosal-associated invariant T (MAIT) cells. Collectively, these advances signal a shift toward adaptable, off-the-shelf, biomarker-guided platforms designed to keep pace with tumor evolution and achieve escape-resistant immunity.
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