LIGHT (TNFSF14), a protein within the tumour necrosis factor (TNF) superfamily, signals through two distinct receptors: HVEM (TNFRSF14), a key costimulatory molecule in T cell activation, and LTβR (TNFRSF3), involved in lymphoid organogenesis and formation of ectopic tertiary lymphoid structures during chronic inflammation.

Despite its therapeutic promise, prior efforts to deliver soluble LIGHT using traditional IgG Fc-fusion constructs yielded functionally inactive proteins, limiting its application in preclinical models.

Research published in the Journal of Molecular Medicine, describes how scientists working to overcome this limitation developed a novel recombinant protein—Ig.Foldon-mLIGHT—by incorporating a small homotrimeric domain (foldon) at the N-terminus of mouse LIGHT (mLIGHT).

This trimeric configuration reflects the natural clustering behavior of TNF family ligands, which is essential for effective receptor engagement. Functional validation using a cell-based reporter assay confirmed that Ig.Foldon-mLIGHT successfully binds and activates both HVEM and LTβR.

They evaluated the immunological and therapeutic potential of this construct using the B16.F10 melanoma model in syngeneic mice. tumours derived from cells expressing membrane-bound mLIGHT displayed growth kinetics similar to mock-transduced controls, indicating limited immunomodulatory effects. In contrast, tumours expressing Ig.Foldon-mLIGHT exhibited significantly delayed growth and were characterized by a pronounced infiltration of dendritic cells and cytotoxic lymphocytes, indicative of enhanced local immune activation.

This study demonstrates that functional trimeric soluble LIGHT can be generated through foldon-mediated trimerization, enabling effective receptor engagement and immune activation. Importantly, this antitumour effect was achieved without the need for prophylactic vaccination using irradiated tumour cells, highlighting the standalone therapeutic potential of Ig.Foldon-mLIGHT.

Given the enhanced immune cell recruitment observed, this strategy holds promise for combination therapies with immune checkpoint inhibitors to further potentiate antitumour responses.

The researchers present a rationally engineered, active soluble form of LIGHT capable of modulating the tumour microenvironment and eliciting potent antitumour immunity. This work lays the foundation for further preclinical and translational studies aimed at harnessing LIGHT as an immunotherapeutic agent.

Article: https://link.springer.com/article/10.1007/s00109-025-02552-x