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

Abstract

Chimeric antigen receptor T (CAR-T) cell therapy has achieved unprecedented clinical success in hematologic malignancies, yet translating these outcomes to solid tumors has proven substantially more challenging. Unlike blood cancers, solid tumors present multiple interconnected barriers, including antigen heterogeneity, inefficient trafficking and infiltration, physical stromal constraints, metabolic competition, and profoundly immunosuppressive tumor microenvironments that collectively limit CAR-T cell persistence and function. Increasing evidence indicates that no single engineering modification is sufficient to overcome these obstacles, driving the development of combination strategies that integrate CAR-T cells with immune checkpoint blockade, cytokine and chemokine modulation, targeted therapies, radiotherapy, oncolytic viruses, cancer vaccines, biomaterial-based delivery platforms, and next-generation synthetic biology approaches. Concurrent advances in armored CAR-T cells, logic-gated circuits, multi-antigen targeting systems, and non-viral gene engineering are enabling more precise, adaptable, and controllable cellular therapies. In this review, we examine the biological mechanisms underlying resistance to CAR-T therapy in solid tumors and critically evaluate emerging combination strategies designed to enhance tumor recognition, trafficking, persistence, and antitumor activity. We further discuss translational challenges, including manufacturing complexity, toxicity management, and patient selection, and propose a framework for developing precision combination CAR-T therapies tailored to the unique biology of individual tumors. Collectively, these advances are reshaping CAR-T cell therapy from a single-agent cellular intervention into a programmable, increasingly integrated platform for solid-tumor immunotherapy.