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  • Challenges and Emerging Strategies of CAR-T Cell Therapy in Solid Tumors: A Narrative Review

  • Shiva Sharestani,1,* Majid Sadeghizadeh,2 Zahra-Soheila Soheili,3 Fatemeh Rahbarizadeh,4
    1. Department of Molecular Genetics, Tarbiat Modares University, Tehran, Iran
    2. Department of Molecular Genetics, Tarbiat Modares University, Tehran, Iran
    3. Department of Medical Genetics, National Institute of Genetic Engineering and Biotechnology (NIGEB), Tehran, Iran
    4. Department of Medical Biotechnology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran


  • Introduction: CAR-T cell therapy has revolutionized the treatment of several hematological malignancies; however, its clinical efficacy in solid tumors remains limited. Tumor antigen heterogeneity, inadequate T-cell trafficking and infiltration, an immunosuppressive tumor microenvironment (TME), T-cell exhaustion, and on-target/off-tumor toxicity are the main obstacles to successful treatment. This narrative review seeks to synthesize current challenges and emerging solutions in CAR-T cell therapy for solid tumors, with a specific focus on next-generation CAR-T platforms and their potential to overcome limitations that have hindered durable and safe clinical responses.
  • Methods: We reviewed recent preclinical and clinical studies on CAR-T cell therapy in solid tumors, focusing on tumor antigen selection, CAR engineering, T-cell trafficking and persistence, the TME, treatment-related toxicity, and emerging combination strategies. We also critically evaluated current evidence on next-generation CAR-T platforms and their potential for clinical translation.
  • Results: Several factors account for the limited efficacy of CAR-T cells in solid tumors. Antigen heterogeneity and antigen loss can cause tumor escape, while physical barriers and abnormal tumor vasculature limit CAR-T-cell trafficking and infiltration. Moreover, the immunosuppressive and metabolically unfavorable elements of the TME lead to T-cell dysfunction, exhaustion, and limited persistence. Emerging strategies to address these obstacles include dual- and multi-antigen targeting, 'armored' CAR-T cells, and logic-gated CAR designs aimed at improving tumor selectivity and reducing antigen escape and off-tumor effects. Engineering approaches to enhance trafficking and immunosuppression resistance, together with local or regional administration and combination therapies (e.g., immune checkpoint inhibitors, radiotherapy, or other TME-modifying approaches), have shown promising results in preclinical and early clinical studies. In a phase 1 trial of CLDN18.2-targeted CAR-T cells (satri-cel/CT041) in 98 patients with advanced gastrointestinal cancers, an objective response rate of 38.8% and a disease control rate of 91.8% were reported, with a median progression-free survival of 4.4 months. However, durable responses remain inconsistent, and issues of safety, target specificity, persistence, manufacturing complexity, and patient selection continue to challenge clinical translation.
  • Conclusion: CAR-T cell therapy is a promising, though still evolving, method for the treatment of solid tumors. Successful clinical translation will likely require an integrated strategy encompassing accurate antigen selection, advanced CAR engineering, improved tumor trafficking, enhanced T-cell persistence, and resistance to immunosuppression. The ongoing development of next-generation CAR-T platforms, together with rational combination therapies, could lead to safer and more durable responses in patients with solid malignancies.
  • Keywords: Immunotherapy; Neoplasms; Receptors, Chimeric Antigen; Tumor Heterogeneity; Tumor Microenvironment

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