Targeting lymphotoxin β receptor: from mechanism to precision therapy

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• The tumour necrosis factor receptor superfamily (TNFRSF) is crucial for immune homeostasis and cell fate.
• Lymphotoxin β receptor (LTβR, TNFRSF3) is a key TNFRSF member expressed on stromal and myeloid cells.
• LTβR signaling regulates immune responses and cell fate decisions.

Purpose of the Study:

• To review the biological features of LTβR.
• To summarize LTβR's dual regulatory roles in the tumour microenvironment (TME).
• To highlight LTβR's potential as a cancer immunotherapy target.

Main Methods:

• Literature review of studies on LTβR signaling.
• Analysis of LTβR's functions in immune homeostasis and TME.
• Evaluation of LTβR agonists in preclinical and clinical studies.

Main Results:

• LTβR activation by lymphotoxin α1β2 (LTα1β2) and TNFSF14 (LIGHT) modulates NF-κB pathways.
• LTβR promotes high endothelial venule and tertiary lymphoid structure formation in the TME.
• LTβR signaling facilitates immune cell recruitment and organization, shaping anti-tumour immunity.

Conclusions:

• LTβR has multifaceted roles in inflammation, lymphoid organogenesis, and TME remodeling.
• LTβR agonists demonstrate therapeutic potential, particularly when combined with immune checkpoint inhibitors.
• LTβR represents a promising novel target for advancing cancer immunotherapy strategies.