UD(PS)-Heptose (L-isomer) - ALPK1 ligand

ALPK1–TIFA signaling and heptose sensing

The alpha kinase 1 (ALPK1)–TRAF-interacting protein with forkhead-associated domain (TIFA) signaling pathway represents a distinct cytosolic innate immune sensing mechanism that detects bacterial heptose metabolites derived from lipopolysaccharide (LPS) biosynthesis in Gram-negative bacteria. Upon cytosolic entry, nucleoside diphosphate heptoses (e.g. ADP-heptose, UDP-heptose) bind to ALPK1, inducing ALPK1 kinase activation and phosphorylation of the adaptor protein TIFA [1]. Phosphorylated TIFA undergoes oligomerization and recruits TNF receptor–associated factor 6 (TRAF6), leading to downstream activation of NF-κB and the transcription of pro-inflammatory cytokines and chemokines [1]. Accordingly, mutations in ALPK1 are associated with retinal dystrophy, optic nerve oedema, splenomegaly, anhidrosis and headache (ROSAH) syndrome [1,2]. 

ADP- and UDP-linked heptose metabolites are susceptible to non-specific hydrolysis, which can limit their stability and reproducibility in experimental systems. Phosphorothioate-modified analogue UD(PS)-Heptose, also referred to as UDSP-Hep, has been developed to overcome these limitations. By substituting a non-bridging phosphate oxygen with sulfur, UD(PS)-Heptose exhibits increased resistance to hydrolysis, enhanced serum stability, and significantly improved potency in activating ALPK1-dependent signaling, resulting in more robust and sustained TIFA phosphorylation and NF-κB activation [3].

UD(PS)-Heptose in antitumor immunity

Recent studies have identified ALPK1 signaling as a key contributor to antitumor immunity. Activation of the ALPK1–TIFA axis by bacterial heptose metabolites induces the production of pro-inflammatory chemokines, notably CXCL10 and CCL2, which promote the recruitment of immune effector cells into the tumor microenvironment. In preclinical models, administration of ALPK1 agonists results in significant tumor control in an ALPK1-dependent manner, as mice lacking ALPK1 fail to mount comparable immune responses [3]. 

Stabilized analogues such as UD(PS)-Heptose exhibit increased potency and serum stability compared with native ADP-heptose, enabling stronger and more sustained ALPK1 activation. In addition to their innate immunostimulatory activity, ALPK1 agonists have been shown to synergize with immune checkpoint blockade. Combining it with anti-CLT4 or PD-1 IC inhibitors resulted in enhanced antitumor efficacy through coordinated activation of dendritic cells, macrophages, and CD8⁺ cytotoxic T cells. These effects critically depend on chemokine-mediated immune cell trafficking, positioning UD(PS)-Heptose as a valuable tool for investigating ALPK1-driven innate-adaptive immune crosstalk and its therapeutic potential in cancer immunology [3].

References:

1. Cohen P. & Snelling T. et al., 2025. Diseases caused by altered specificity of a protein kinase for its allosteric activators. Trends Biochem Sci. 50(1):61-70
2. Kozycki C. et al., 2022. Gain-of-function mutations in ALPK1 cause an NFκB-mediated autoinflammatory disease: functional assessment, clinical phenotyping and disease course of patients with ROSAH syndrome. Ann Rheum Dis. 81:1453-1464
3. Tian X. et al., 2025. Agonists for cytosolic bacterial receptor ALPK1 induce antitumour immunity. Nature.