肿瘤细胞治疗研究
英文原题：Next-generation CAR-T engineering for colorectal cancer: integrating targets, tumor microenvironment barriers, and emerging strategies.
结直肠癌（CRC）的嵌合抗原受体（CAR）-T细胞治疗面临三大障碍：抗原异质性、脱靶毒性和疗效-安全性权衡。
嵌合抗原受体（CAR）-T 细胞治疗结直肠癌（CRC）面临三大障碍：抗原异质性、脱靶毒性和疗效-安全性权衡。为克服这些障碍，下一代工程策略已经出现，包括：（1）具有更好组织限制性的新型 CRC 相关靶点；（2）结构创新，如 armored CAR、优化信号传导（1XX、28- IL2RB-z(YXXQ)）和细胞因子武装；（3）组合抗原感知回路（AND/OR/NOT 门、SUPRA、synNotch）；以及（4）基于 CRISPR 的编辑，用于耗竭相关基因敲除（如 PD-1、Fas、TGFBR2）和位点特异性 CAR 敲入。临床证据已在部分患者中显示客观缓解和疾病稳定。然而，免疫抑制性肿瘤微环境——包括抑制性细胞、致密基质和代谢功能障碍——仍是限制 CAR-T 持久性的关键障碍。未来方向应优先考虑分子分型指导的干预、通用 CAR-T、多细胞平台（CAR-NK、CAR-M）和跨学科合作。本综述为设计能够在晚期 CRC 中实现持久缓解的下一代 CAR-T 疗法提供了框架。
Chimeric antigen receptor (CAR)-T cell therapy for colorectal cancer (CRC) faces three major barriers: antigen heterogeneity, off-tumor toxicity, and the efficacy-safety trade-off. To overcome these obstacles, next-generation engineering strategies have emerged, including: (1) novel CRC-associated targets with improved tissue restriction; (2) architectural innovations such as armored CARs, optimized signaling (1XX, 28- IL2RB-z(YXXQ)), and cytokine-arming; (3) combinatorial antigen-sensing circuits (AND/OR/NOT gates, SUPRA, synNotch); and (4) CRISPR-based editing for exhaustion-related knockouts (e.g., PD-1, Fas, TGFBR2) and site-specific CAR knock-in. Clinical evidence has demonstrated objective responses and disease stabilization in subsets of patients. However, the immunosuppressive tumor microenvironment-including inhibitory cells, dense stroma, and metabolic dysfunction-remains a critical hurdle limiting CAR-T persistence. Future directions should prioritize molecular typing-guided intervention, universal CAR-T, multicellular platforms (CAR-NK, CAR-M), and interdisciplinary collaboration. This review provides a framework for designing next-generation CAR-T therapies capable of achieving durable remissions in advanced CRC.
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