Lymphotoxin alpha (LTA) is a multifunctional cytokine produced by lymphocytes that operates through distinct receptor interactions. In its homotrimeric form, LTA binds to TNF receptors (TNFRSF1A, TNFRSF1B, and TNFRSF14/HVEM), while its heterotrimeric complex with lymphotoxin-beta engages TNFRSF3/LTBR 12. LTA executes cytotoxic functions against tumor cells and promotes extrinsic apoptosis through NF-κB and JAK-STAT signaling pathway activation 3. Mechanistically, LTA triggers canonical and noncanonical NF-κB cascades alongside JAK2/STAT6 signaling, which reciprocally activates LTA and TNFRSF14 expression, establishing positive feedback loops 3. LTA modulates immune responses by inducing pro-inflammatory cytokine production (IL-6, TNFα) and regulating immune checkpoint molecules, including PD-L1/PD-L2 and adhesion factors 3. Clinically, LTA polymorphisms demonstrate cancer risk associations: rs2239704 shows protective effects against overall cancer and non-Hodgkin lymphoma, while rs909253 increases hepatocellular carcinoma susceptibility in Caucasians 4. In malignancy, autocrine LTA signaling drives persistent NF-κB activation in Hodgkin lymphoma cells, providing rationale for LTA-targeted therapeutics 3. Beyond oncology, LTA from gram-positive bacteria stimulates inflammatory responses in corneal epithelial cells through NF-κB/MAPK pathways, though this effect can be mitigated by the ubiquitin-editing enzyme A20 5.