HHLA2 and TMIGD2 Pathway

As a novel immune checkpoint, HHLA2 plays a dual role in immune suppression and stimulation during tumor development. Here, Creative Biolabs focuses on introducing the HHLA2-TMIGD2 co-stimulatory pathway, and provides a reliable and comprehensive theoretical basis while offering an all-inclusive service package.

Structure and Expression of HHLA2

HHLA2 belongs to the B7 family of type I transmembrane proteins and consists of a transmembrane region, cytoplasmic tail, and extracellular portion composed of consecutive IgV1-IgCIgV2 domains, totaling 414 amino acids. HHLA2 is mainly expressed on various types of antigen-presenting cells (APCs) and tumor cells, including monocytes and activated B cells.

Structure and Expression of TMIGD2

TMIGD2 is a single-pass transmembrane protein responsible for cell adhesion and migration, characterized by a single IgV domain in its extracellular region and a cytoplasmic tail. TMIGD2 is expressed on immature T cells, tissue-resident T cells, NK cells, and innate lymphoid cells, but its expression gradually diminishes with T cell/NK cell activation and differentiation.

HHLA2 immune pathway. (Li, et al., 2023)Fig 1. HHLA2 immune pathway.1

HHLA2-TMIGD2 Pathway in Immune Responses

The interaction between HHLA2 and TMIGD2 acts as an immune stimulatory checkpoint, enhancing T cell proliferation and cytokine production. Generally, the HHLA2-TMIGD2 pathway functions through the following mechanisms:

  • HHLA2/TMIGD2 co-stimulation induces T cell activation and proliferation via the AKT pathway.
  • HHLA2/TMIGD2 interaction enhances CD16-mediated NK cell cytotoxicity and ADCC, promoting NK cell activation.
  • TMIGD2 synergizes with 2B4 and NKp46 to induce degranulation, cell lysis, and cytokine secretion.

In addition, HHLA2 plays a dual role in regulating tumor immune responses. Besides its binding with TMIGD2 to initiate immune stimulation, it also interacts with KIR3DL3, resulting in immune inhibitory effects.

HHLA2/TMIGD2 Immunotherapy

Immune checkpoint blockade has revolutionized tumor therapy as a promising intervention. HHLA2, as a potentially effective immune checkpoint pathway, has been under development. Key strategies currently being explored are:

  • Blocking HHLA2/KIR3DL3 without interrupting the co-stimulatory signals of HHLA2-TMIDG2 is considered a promising anti-tumor strategy.
  • Combination therapies that further enhance the HHLA2-TMIDG2 signal or simultaneously manipulate the HHLA2-KIR3DL3/TMIGD2 interaction have shown certain efficacy in animal models.
  • The non-overlapping expression of HHLA2 and PD-L1 makes HHLA2 a preferred alternative option for patients resistant to PD-1 blockade.

Unfortunately, there have been no completed clinical trials directly targeting HHLA2 or its receptors. However, it is undeniable that the HHLA2-TMIDG2 pathway remains a potential and effective alternative for immune checkpoint-based anti-tumor strategies.

Our Services

Creative Biolabs' commitment to providing a comprehensive range of services goes beyond theoretical support. We offer tailored solutions and cutting-edge technologies to address your unique challenges in the field of immune checkpoint research. Our team of experts is dedicated to partnering with you, ensuring the highest level of excellence and success in your scientific endeavors. Contact us now to explore the full potential of immune checkpoint immunotherapy.


  1. Li, Lv, et al. "KIR3DL3-HHLA2 and TMIGD2-HHLA2 pathways: The dual role of HHLA2 in immune responses and its potential therapeutic approach for cancer immunotherapy." Journal of Advanced Research. 47 (2023): 137-150.

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