Targeting lymphotoxin β receptor: from mechanism to precision therapy

The tumour necrosis factor receptor superfamily (TNFRSF) represents a pivotal signalling network that orchestrates immune homeostasis and regulates cell fate decisions. Lymphotoxin β receptor (LTβR, TNFRSF3), a key TNFRSF member, is predominantly expressed on stromal cells and distinct myeloid subsets. Upon binding to its ligands lymphotoxin α1β2 (LTα1β2) and TNFSF14 (LIGHT), LTβR activates multiple signalling cascades, including canonical and non-canonical NF-κB pathways, thereby playing an essential role in tumour immune regulation. LTβR exerts multifaceted functions in lymphoid organogenesis, chronic inflammation, and tumour microenvironment (TME) remodelling. Notably, it promotes the formation of high endothelial venules and tertiary lymphoid structures, facilitating immune cell recruitment and spatial organisation to shape anti-tumour immunity. Recent studies highlight that LTβR agonists show promising therapeutic potential, particularly in combination with immune checkpoint blockade. This review summarises the biological features of LTβR and its dual regulatory roles in the TME, underscoring its potential as a novel target for cancer immunotherapy.