Review Article: Overcoming Antigen Expression Barriers in CAR-T Therapy for Solid Tumors

Chimeric antigen receptor T cell (CAR-T) therapy has transformed the treatment landscape for hematologic malignancies, achieving deep and durable responses across multiple FDA approved products. This progress stems from foundational discoveries initiated by Zelig Eshhar, whose early demonstrations that T cells could be redirected using synthetic receptors laid the conceptual groundwork for modern CAR-T design. Despite these successes, translating CAR-T therapy into solid cancers remains challenging. Solid tumors present unique obstacles including antigen heterogeneity, immunosuppressive microenvironments, limited T cell trafficking, and multiple mechanisms of antigen escape. Case studies across key solid tumor targets such as mesothelin, interleukin 13 receptor alpha 2 (IL13Rα2), claudin 18.2 (CLDN18.2), glypican 3 (GPC3), epithelial cell adhesion molecule (EpCAM), human epidermal growth factor receptor 2 (HER2), and ganglioside D2 (GD2) highlight both the promise of CAR-T therapy and the biological complexities that limit durable clinical benefit. To address these barriers, next generation engineering strategies incorporating multispecific targeting, adaptor platforms, and logic gated receptor circuits (OR, AND, NOT, and multi-layered designs) are being developed to enhance tumor specificity, mitigate on-target/off-tumor toxicity, and prevent antigen escape. Armored CAR-T cells capable of overcoming suppressive tumor microenvironments further expand therapeutic potential. Collectively, these advances signal a shift from single antigen targeting to programmable, modular T cell therapies capable of responding to the multifaceted challenges of solid tumors. As the field integrates synthetic biology innovations with lessons learned from decades of clinical practice, CAR-T therapy is poised for broader applicability across both hematologic and solid cancers, extending the legacy of Eshhar's pioneering work.