Targeting the MHC-I endosomal-lysosomal trafficking pathway in cancer: From mechanism to immunotherapy

Area of Science:

• Immunology
• Oncology
• Molecular Biology

Background:

• Immune checkpoint blockade (ICB) therapy shows promise but faces suboptimal response rates due to innate resistance.
• Low CD8+ cytotoxic T cell (CTL) infiltration, linked to insufficient antigen presentation, is a key factor in ICB resistance.
• Major histocompatibility complex class I (MHC-I) expression on tumor cells is crucial for CTL recognition and tumor clearance.

Purpose of the Study:

• To review mechanisms of membrane MHC-I translocation into the cytoplasm and lysosomal degradation.
• To highlight how tumor cells evade CTL detection and clearance by modulating MHC-I expression.
• To summarize novel therapeutic strategies targeting these pathways for improved cancer immunotherapy.

Main Methods:

• Literature review of recent advances in endosomal-lysosomal MHC-I transport.
• Analysis of tumor cell mechanisms for reducing surface MHC-I expression.
• Synthesis of current knowledge on therapeutic interventions targeting MHC-I pathways.

Main Results:

• Tumor cells employ various mechanisms to reduce surface MHC-I, impairing antigen presentation and immune evasion.
• Endosomal-lysosomal pathways play a significant role in regulating MHC-I surface expression and stability.
• Targeting MHC-I trafficking and degradation presents a potential strategy to overcome ICB resistance.

Conclusions:

• Understanding MHC-I regulation is critical for improving ICB efficacy.
• Therapeutic strategies targeting MHC-I lysosomal degradation may enhance anti-tumor immunity.
• This review provides insights into optimizing cancer immunotherapy by modulating MHC-I pathways.