Engineering CAR-T cells for solid tumors: overcoming antigenic, trafficking, and microenvironmental barriers

Reprogramming CAR-T Cell Therapy for Solid Tumors: Combination Strategies to Overcome Resistance

The biological mechanisms underlying resistance to CAR-T therapy in solid tumors are examined and emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity are critically evaluated.

Expanding the Horizon of CAR-T Cell Therapy: Present Obstacles and New Strategies for Future CARs in Solid Tumors.

Chimeric antigen receptor (CAR)-T cells are synthetic receptors used for the recognition of specific antigens expressed by reprogrammed T cells for targeting tumors. CAR-T cell therapy has gained remarkable clinical success for the treatment of hematological malignancies such as chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), lymphoplasmacytic lymphoma (LPL), and primary intraocular lymphoma (PIL). The increasing number of preclinical investigations and clinical trials is focusing on extending CAR-T cell therapy to solid tumors due to its remarkable success in leukemia and lymphoma cancers. However, some limitations of CAR-T therapy still exist, including a lack of targetable antigen diversity, heterogeneous antigen expression, insufficient T-cell trafficking efficiency, and an immunosuppressive tumor microenvironment. This review explores the role of CAR-T cell therapy, current challenges, and emerging solutions for solid tumor malignancies. To overcome the existing limitations of CAR-T cell therapy, innovative strategies, including the optimization of novel CAR vectors with checkpoint inhibitors, have been designed to enhance the antitumor activity of CAR-T cells against solid tumors. It also explores the design of novel CAR-T cells and strategies for improving antitumor activity against solid tumors. Among the emerging strategies, universal CARs and combination approaches with checkpoint inhibitors are especially promising for extending CAR-T therapy to solid tumors.

Immunological barriers and engineering strategies for CAR-T cell therapy in acute myeloid leukemia

These major barriers to effective CAR-T therapy in AML are discussed and emerging engineering strategies developed to address them are summarized, including approaches to improve targeting precision, reinforce CAR-T cell functional fitness, and remodel the suppressive immune niche.

CAR-T Cell Therapy for Glioblastoma: Obstacles and Advances.

Glioblastoma (GBM) is the most aggressive primary malignancy of the central nervous system. Chimeric antigen receptor T (CAR-T) cell therapy has shown promising therapeutic potential against GBM, yet its efficacy remains constrained by multiple barriers, including physical barriers imposed by the blood-brain barrier and extracellular matrix, the immunosuppressive tumor microenvironment, spatiotemporal antigen heterogeneity, and safety concerns. In this review, we summarize the major obstacles limiting CAR-T therapy in GBM and discuss emerging strategies to overcome these challenges. Next-generation engineered CAR-T cells-through armored modifications, logic-gated regulation, and dual-targeting approaches-enhance specificity, persistence, and controllability. Concurrently, combinatorial approaches leveraging biomaterials enable localized delivery and sustained release of CAR-T cells, while physical modalities, such as focused ultrasound and thermal modulation, can transiently disrupt the blood-brain barrier or induce immunogenic cell death. Integration with real-time imaging further enables dynamic monitoring of therapeutic responses. Together, these synergistic strategies may enhance antitumor efficacy while minimizing systemic toxicity, paving the way for future CAR-T-based therapies in glioblastoma.

T-Cell-Based Immunotherapy for Solid Tumors: Challenges, Mechanisms, and Combination Strategies

T-cell-based immunotherapy has become a key approach in cancer treatment, based on the principle of utilizing immune cells to recognize and eliminate malignant cells. However, compared to certain hematologic malignancies, the response of solid tumors to this type of therapy remains suboptimal. This article outlines the biological mechanisms underlying CD8+ T-cell-mediated tumor killing and explores the major limitations faced by T cells in the treatment of solid tumors, including a limited number of tumor-specific antigens, poor tumor infiltration capacity, an immunosuppressive microenvironment, metabolic stress, and T-cell exhaustion. In addition, this article introduces adoptive T-cell therapy, CAR-T therapy, TCR-T therapy, and PD-1/PD-L1 immune checkpoint blockade therapy, emphasizing the importance of combination treatment strategies. The article also discusses antigen-specific systems such as the OT-I/B16-OVA model, which serve as important tools for studying T-cell killing mechanisms and immune evasion. Progress in this field will depend on enhancing the T cells’ specificity, persistence, and tumor homing ability, as well as their capacity to overcome inhibitory mechanisms, while ensuring clinical safety.

T cell-based immunotherapy in solid tumors: mechanistic barriers and emerging opportunities.