Targeting molecular pathways to control immune checkpoint inhibitor toxicities

Area of Science:

• Oncology
• Immunology
• Pharmacology

Background:

• Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy.
• Immune-related adverse events (irAEs) are common and can affect multiple organ systems.
• The molecular underpinnings of irAEs require further elucidation.

Purpose of the Study:

• To synthesize preclinical and clinical findings on the molecular mechanisms of irAEs.
• To identify key immune cells, signaling pathways, and factors involved in irAE pathogenesis.
• To explore novel therapeutic strategies for mitigating irAEs while preserving ICI efficacy.

Main Methods:

• Comprehensive review of preclinical and clinical studies on irAEs.
• Analysis of immune cell subsets (T cells, myeloid cells) in irAE development.
• Examination of cytokine signaling (e.g., IL-6, IFN-γ, TNF-α), integrin interactions, and microbiome influences.

Main Results:

• T cell subsets and myeloid cells play critical roles in irAE pathogenesis.
• Specific cytokine signaling pathways (IL-6, IL-17, IL-4, IFN-γ, IL-1β, TNF-α) are implicated in irAEs.
• Integrin-mediated interactions and microbiome dysbiosis contribute significantly to irAE pathology.

Conclusions:

• Understanding irAE molecular drivers offers opportunities for targeted mitigation strategies.
• Antibodies targeting key inflammatory molecules may reduce irAEs.
• Therapeutic interventions should aim to balance irAE management with sustained ICI antitumor activity.