HEPHAISTOS is a preclinical-stage biopharmaceutical company focused on designing and developing a third-generation innate immune activator. Its mission is to address a major challenge in oncology: improving patient responses to existing immunotherapies by overcoming myeloid-driven tumor immunosuppression.

The company’s lead candidate, HEPHA-440, enhances antitumor activity through multiple mechanisms. It promotes the recruitment of immune effector cells into the tumor microenvironment (TME), reverses macrophage polarization, activates dendritic cells and antigen presentation, and triggers CD8 T-cell–mediated cytotoxicity.

HEPHA-440 is an engineered small-molecule TLR4 agonist of the third generation. Compared to earlier clinical-stage compounds such as GLA and GSK1795091, it is 30 to 400 times safer, and it is twice as effective as first-generation molecules like GLA and MPL. It is also suitable for intravenous administration.

Preclinical studies have shown that HEPHA-440 achieves a balanced MyD88–TRIF signaling profile that favors antitumor cytokine production while maintaining low pyrogenicity. It has demonstrated strong single-agent efficacy, including complete tumor regressions and systemic effects against metastases. In combination therapies, it shows synergy with anti-PD-1 and anti-CD20 antibodies, achieving up to 100% complete tumor regression in some models. Additionally, it significantly increases PD-1 and PD-L1 expression within the tumor microenvironment.

HEPHAISTOS has been awarded funding from the EIC Accelerator ($3 million) and the France 2030 RHU program ($11.5 million), and has also received recognition from Sanofi and Amgen through their Golden Ticket programs.