TNFSF14 is a TNF superfamily cytokine that delivers costimulatory signals to T cells through binding to its cognate receptor TNFRSF14/HVEM, promoting T cell proliferation and interferon-gamma production. The protein can also engage the decoy receptor TNFRSF6B and the lymphotoxin-beta receptor TNFRSF3, modulating its immunological effects across both innate and adaptive immunity. At the tissue level, TNFSF14 regulates diverse inflammatory and fibrotic processes. In inflammatory bowel disease, dysregulated TNFSF14 expression by activated mesenchymal populations contributes to epithelial barrier dysfunction and oxidative stress 1. In the heart, TNFSF14 promotes atrial fibrillation vulnerability by driving M2 macrophage polarization through the PI3Kγ/SGK1 pathway, and elevated serum TNFSF14 correlates with atrial fibrosis in patients with atrial fibrillation 2. In reproduction, decidual NK cells suppress stromal cell senescence via TNFSF14-TNFRSF14 signaling, and insufficient TNFRSF14 expression associates with recurrent spontaneous abortion 3. Clinically, TNFSF14 expression is elevated in glioblastoma and correlates with immunosuppressive markers including regulatory T cells and PD-L1 4. In steatotic liver disease-related hepatocellular carcinoma, blocking TNFRSF14 reduced regulatory T cells and enhanced anti-programmed cell death protein 1 therapy efficacy 5. In colorectal cancer, engineered bacteria expressing TNFSF14 induced tertiary lymphoid structures and antitumor immunity through HVEM signaling on innate lymphoid cells 6. QUISOVALIMAB and BAMINERCEPT, which target TNFSF14 and its receptors, represent therapeutic approaches to modulate this axis in disease.