Review describes biological barriers to CAR-T therapy in solid tumors and engineering strategies

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic malignancies by enabling antigen-specific tumor targeting and durable clinical responses. However, its translation to solid tumors has been limited by fundamental biological barriers, including antigen heterogeneity, poor tumor infiltration, and profound immunosuppressive and metabolic constraints within the tumor microenvironment. These factors collectively drive CAR-T cell dysfunction, exhaustion, and limited persistence, resulting in modest and inconsistent clinical efficacy. This review provides a concept-driven synthesis of recent advances in CAR-T cell therapy for solid tumors, with a specific focus on systems-level engineering strategies that integrate tumor biology, spatial context, and cellular metabolism. We highlight emerging approaches such as in vivo 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.