Targeting solid tumors with TCR-T cells: mechanisms, progress, and challenges

Area of Science:

• Oncology
• Immunology
• Cellular Therapy

Background:

• T-cell receptor-engineered T-cell (TCR-T) therapy targets intracellular antigens via peptide-human leukocyte antigen (pHLA) complexes, expanding treatment beyond surface proteins.
• Clinical activity in solid tumors is inconsistent due to HLA restriction, antigen heterogeneity, presentation instability, and immunosuppressive tumor microenvironments.

Purpose of the Study:

• To review the biological basis of TCR-T therapy in solid tumors.
• To summarize current clinical progress and identify barriers to durable tumor control.
• To discuss emerging strategies for enhancing TCR-T therapeutic performance.

Main Methods:

• Review of biological mechanisms of TCR-T therapy, including pHLA recognition and tumor cell killing.
• Analysis of current clinical data across various solid tumor types.
• Discussion of emerging engineering and manufacturing strategies.

Main Results:

• TCR-T therapy demonstrates meaningful responses in specific biomarker-defined settings but limited efficacy in many epithelial cancers.
• Durable tumor control requires more than target recognition, depending on antigen presentation, T-cell trafficking, and overcoming suppressive signals.
• Emerging strategies focus on precision engineering, multi-HLA targeting, and microenvironment modulation.

Conclusions:

• TCR-T therapy offers a promising framework for solid tumor treatment.
• Broader and more durable benefits necessitate integrated advances in target selection, safety, and cellular engineering.
• Overcoming antigen presentation barriers and immunosuppression is crucial for clinical success.