ReviewFrontiers in immunology2026
Next-generation CAR-T engineering for colorectal cancer: integrating targets, tumor microenvironment barriers, and emerging strategies.
Review in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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7 authors.
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Abstract
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-ΔIL2RB-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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