T-Cell Exhaustion in the Tumor Microenvironment: Subcellular Dysfunction, Pan-Cancer Characteristics, and Therapeutic...

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Immune checkpoint blockade (ICB) therapy is crucial for cancer treatment.
• T-cell exhaustion (Tex) limits ICB efficacy in solid tumors.
• Subcellular organelle dysfunction in T cells within the tumor microenvironment (TME) is understudied.

Purpose of the Study:

• To review the role of subcellular organelle dysfunction in T-cell exhaustion.
• To explore how organelle interactions contribute to T-cell dysfunction.
• To summarize therapeutic strategies targeting organelle checkpoints.

Main Methods:

• Systematic review of literature on T-cell exhaustion and organelle function.
• Analysis of organelle interaction networks (mitochondria, ER, nucleus, lysosomes).
• Summary of T-cell subcellular dysfunction across different solid tumors.

Main Results:

• Suborganellar dysfunction is a key driver of T-cell exhaustion.
• Dysregulated organelle networks (mitochondria, ER, nucleus) create a self-sustaining cycle of T-cell dysfunction.
• Specific organelle defects are observed in various solid tumors, including lung and liver cancers.

Conclusions:

• Subcellular organelle dysfunction is a critical mechanism underlying T-cell exhaustion.
• Targeting organelle homeostasis and function presents promising therapeutic avenues.
• Subcellular engineering approaches can enhance T-cell-mediated anti-tumor immunity.