From Bench to Bedside: Emerging Paradigms in CAR-T Cell Therapy for Solid Malignancies.

Immunotherapy, particularly chimeric antigen receptor T cell (CAR-T) therapy, has revolutionized the treatment of hematological malignancies and autoimmune diseases. However, its efficacy in solid tumors remains limited due to challenges such as tumor heterogeneity, an immunosuppressive microenvironment, and poor T cell infiltration. This review first summarizes the primary causes and challenges that restrict CAR-T therapy in the treatment of solid tumors, followed by an overview of recent advancements in gastric cancer, liver cancer, and glioma, where early trials have demonstrated promising clinical potential. Advances in CRISPR-edited and "off-the-shelf" allogeneic CAR-T cells seek to improve scalability, while artificial intelligence (AI)-driven target discovery, synthetic biology, and cytokine armoring strategies aim to enhance tumor specificity and T-cell persistence. Additionally, the flexible utilization of combination strategies in clinical surgical and medical trials, such as combining CAR-T therapy with immune checkpoint inhibitors, oncolytic viruses, chimeric antigen receptor NK cells (CAR-NK), or chimeric antigen receptor macrophage cells (CAR-M) may further enhance antitumor efficacy. The evolution of CAR-T therapy highlights its potential to reshape precision oncology, offering hope to patients with aggressive solid tumors through ongoing basic research, technological optimization, and clinical refinement.