Emerging mechanisms and targetable pathways in immune checkpoint inhibitor‑associated thyroid dysfunction: From...

Area of Science:

• Oncology
• Immunology
• Endocrinology

Background:

• Immune checkpoint inhibitors (ICIs) enhance anti-cancer immunity but can lead to immune-related thyroid dysfunction (ICI-TD).
• ICI-TD presents with diverse clinical manifestations, ranging from subclinical changes to thyroid storm, stemming from immune tolerance breakdown and autoreactive responses.
• Different ICIs (e.g., anti-PD-1/PD-L1, anti-CTLA-4) exhibit distinct thyroid toxicity profiles, with combination therapies potentially increasing risks and accelerating onset.

Purpose of the Study:

• To systematically review the mechanisms underlying ICI-TD.
• To explore emerging targeted strategies for managing ICI-TD.
• To propose a novel "mechanism-prediction-intervention" framework for optimizing ICI-TD management.

Main Methods:

• Systematic review of emerging mechanisms including immune cell interactions, epigenetic regulation, and the gut-thyroid axis.
• Review of targeted therapeutic strategies such as conditionally activated antibodies, Fc engineering, chemokine receptor targeting, and cytokine neutralization.
• Conceptualization of a predictive and interdisciplinary management framework.

Main Results:

• ICI-TD mechanisms involve complex immune cell crosstalk, epigenetic modifications, and the gut-thyroid axis.
• Novel therapeutic strategies show promise for mitigating ICI-TD.
• Current management is often reactive, relying on monitoring and hormone replacement, with delayed interventions.

Conclusions:

• A "mechanism-prediction-intervention" framework integrating multi-omics data can enable early warning and hierarchical management of ICI-TD.
• This approach is expected to optimize the risk-benefit ratio of immunotherapy.
• Implementing this framework will enhance the safety and efficacy of cancer immunotherapy.