CAR-T cells in solid tumors: engineering, biomarkers, translational pathways and the road ahead

CAR programming, logic-gated and multi-antigen receptor designs, and armored CAR-T cells engineered to resist immunosuppression and metabolic stress. Importantly, this review goes beyond descriptive engineering advances by emphasizing the growing role of computational modeling, artificial intelligence, and spatial multi-omics in guiding antigen selection, CAR circuit design, and predictive assessment of therapeutic responses. Unlike prior reviews that primarily summarize antigen targets or CAR engineering strategies, this review integrates biological barriers in solid tumors with emerging engineering solutions to provide a conceptual framework for the development and clinical translation of next-generation CAR-T therapies. By integrating biological determinants of failure with rational engineering solutions, the review delineates translational pathways that link mechanistic insight to clinical implementation. This review advances the field by framing CAR-T therapy for solid tumors as a systems engineering challenge rather than a single-target optimization problem. By integrating immunology, bioengineering, computational sciences, and spatial biology, we outline a roadmap for the development of safer, more durable, and context-aware CAR-T therapies. Continued progress will depend on tumor-specific antigen discovery, interdisciplinary collaboration, and scalable manufacturing and regulatory frameworks, collectively enabling the next generation of effective CAR-T therapies for solid tumors.