HVEM Immune Checkpoint Molecule for Drug Development

Overview of HVEM

HVEM, also known as TNFR superfamily 14 (TNFRSF14), herpes virus entry mediator A (HveA), another TNFR associated factor-associated receptor, TNF receptor-like molecule 2 (TR2), or LIGHT receptor (LIGHTR), was first identified as a molecule that interacts with herpes simplex virus through viral gD to facilitate viral entry.

Checkpoint receptor Alternate name Ligands
HVEM TNFRSF14, HveA, TR2, LIGHTR, CD270, Another TNFR associated factor-associated receptor LTα, LIGHT, BTLA, and CD160
  • Expression
  • HVEM is widely expressed in nearly all internal organs, with the highest expression in the lung, kidney, liver, and low expression in the heart, placenta, skeletal muscle, pancreas, and brain. The cellular distribution of HVEM is wide, and T cells, B cells, dendritic cells (DCs), as well as all other types of cells within the lymphoid tissue can express HVEM. HVEM expression on naive T cells is high and decreases at an early activation stage but is upregulated at the late activation stage.

  • Pathway
  • HVEM interacts with multiple ligands expressed in the immune system, including the TNF superfamily cytokines, LTα and LIGHT, and the immunoglobulin superfamily members BTLA and CD160. LIGHT binds HVEM at its CRD2 and three regions, which is the main characteristic of interaction between TNF ligand and TNFR proteins. BTLA and CD160 both bind HVEM at its CRD1 domain, at a topologically distinct surface from the TNF ligands. HVEM serves both as a signaling receptor activated by its ligands and as a ligand to activate BTLA and CD160 signaling. Co-expression of HVEM with either BTLA or CD160 results in forming a cell-surface complex in cis that prevents binding of ligands in trans.

Major signaling pathways activated by HVEM network proteins. Fig.1 Major signaling pathways activated by HVEM network proteins. (Sedy, 2019)

HVEM Network-Targeting Immunotherapy

Checkpoint blockade therapy designed to disrupt CTLA-4 and PD-1 signaling provides durable responses for a subset of patients and cancers. However, a substantial proportion of patients do not respond to these immunotherapies, necessitating the development of novel cancer treatments, including additional immunotherapies targeting a broader spectrum of inhibitory receptors alone and in combination with established therapies. Many such drugs are currently being evaluated in experimental models and in clinical trials to increase success rates in treatable cancers and intractable cancers. The HVEM network of receptors and ligands has long been viewed as potentially druggable in cancer, but only recently have HVEM network-targeting immunotherapies entered into pharma pipelines. In contrast, multiple efforts have been made to block inflammatory functions of HVEM network proteins in autoimmune diseases.

Services at Creative Biolabs

Creative Biolabs is a professional immune checkpoint drug development service provider with years of experience accumulated from step-by-step practice. With strong foundations and professional expertise, we are now capable of providing a series of high-quality HVEM immune checkpoint drug development services, including but not limited to:

If you are interested in any of our services, please do not hesitate to contact us for more information.


  1. Sedy, J. R.; Ramezani-Rad, P. HVEM network signaling in cancer. Adv Cancer Res. 2019, 142: 145-186.

All listed customized services & products are for research use only, not intended for pharmaceutical, diagnostic, therapeutic, or any in vivo human use.