Next generation CAR-T cells to tackle solid tumors.

The genetic modification of human T cells to express chimeric antigen receptors (CAR-T cells) has revolutionized cancer immunotherapy by redirecting their cytotoxicity towards specific tumor antigens. While CAR-T cell therapies have demonstrated remarkable success in hematological malignancies, their translation to solid tumors remains limited by several challenges. These include the lack of exclusive tumor antigens and intrinsic tumor heterogeneity, which contribute to suboptimal targeting and increase the risk of on-target, off-tumor effects. Additionally, solid tumors present a complex and hostile tumor microenvironment (TME), characterized by multiple physical barriers and immunosuppressive mechanisms that severely hinder CAR-T cells trafficking, persistence, and anti-tumor activity. A deeper understanding of these obstacles has fueled the development of next-generation CAR designs equipped with advanced synthetic biology approaches. Improved antigen specificity with logic-gated systems, multiple-input CAR designs, co-expression of cytokine receptors, armored CARs, and engineered resistance to immunosuppressive cues in the form of chimeric switch or dominant negative receptors have emerged in response. In this context, this review provides a stepwise and comparative overview of the major biological and structural challenges limiting CAR T-cells efficacy in solid tumors. It critically discusses the innovative CAR constructs developed to overcome each of these obstacles - from antigen selection to trafficking and TME remodeling - offering a forward-looking framework to guide future research and accelerate the translation of CAR-T therapies beyond blood cancers.