Agonists for cytosolic bacterial receptor ALPK1 induce antitumour immunity

Article Meta

Article Date = 10 December 2025
Article URL = https://www.nature.com/articles/s41586-025-09828-9
Article Title = Agonists for cytosolic bacterial receptor ALPK1 induce antitumour immunity
Article Image = (none provided)

Summary

This Nature paper reports that small-molecule and nucleotide-sugar agonists of the cytosolic bacterial-sensing kinase ALPK1 (notably ADP-Hep and a chemically stabilised analogue UDSP-Hep) activate innate immune pathways and provoke potent antitumour immunity in multiple mouse models. The authors show ALPK1 activation triggers TIFA phosphorylation, NF-κB signalling and a broad cytokine response, inflames tumours, recruits and activates dendritic cells, NK cells and CD8+ T cells, and improves tumour control. UDSP-Hep is more stable and more potent than ADP-Hep. Antitumour effects are ALPK1-dependent, require chemokines and bone-marrow derived cells, and can synergise with checkpoint inhibitors and other innate agonists (STING/TLR). The study includes mechanistic work (scRNA-seq, cytokine profiling, knockout and chimera models), chemical optimisation and preclinical therapeutic experiments.

Key Points

ALPK1 senses bacterial ADP-heptose; synthetic agonists (ADP-Hep and UDSP-Hep) activate this innate receptor to induce inflammation and antitumour immunity.
UDSP-Hep is a chemically modified analogue with greater potency and serum stability than ADP-Hep, and shows superior in vivo activity.
Antitumour responses require ALPK1, chemokine signalling (eg CXCL10/CXCR3, CCL2) and bone marrow–derived immune cells; tumours become inflamed and infiltrated by activated DCs, NK cells and CD8+ T cells.
ALPK1 agonists can synergise with checkpoint blockade (anti-PD-1, anti-CTLA-4, anti-4-1BB) and with STING/TLR agonists to enhance tumour control, including in advanced tumours.
Data include scRNA-seq and multiple knockout, depletion and chimera experiments that define cellular requirements and the mechanism of action.
Translational potential is highlighted, but ALPK1 biology links to autoinflammatory syndromes, so therapeutic safety and on-target inflammatory toxicity will need careful evaluation.

Content summary

The authors synthesised ADP-heptose analogues, identified UDSP-Hep as a more potent and stable ALPK1 agonist, and verified ALPK1 activation by measuring TIFA phosphorylation and NF-κB reporter responses. In vitro ADP-Hep/UDSP-Hep stimulated cytokine production from human PBMCs and immune cell lines. In mice, systemic or local delivery inflamed tumours, increased chemokines (eg CXCL10, CCL2), and promoted infiltration and activation of dendritic cells, NK cells and CD8+ T cells. Tumour control was lost in Alpk1 knockout mice and required bone-marrow derived ALPK1 expression. Peri‑tumoural or intratumoural UDSP-Hep reduced growth of multiple tumour types and enhanced survival. Combining UDSP-Hep with immune checkpoint inhibitors or other innate agonists produced additive or synergistic antitumour effects and in some cases cleared tumours and generated long‑lived tumour-specific memory T cells. The paper provides supporting scRNA-seq datasets and GEO accessions for transcriptomic data and includes extended data defining cytokine, pharmacokinetic and biodistribution profiles.

Context and relevance

This work places ALPK1 alongside other innate immune sensors under active investigation for cancer therapy (eg STING, TLRs). It demonstrates a new mechanism to inflame otherwise cold tumours and recruit cross-presenting dendritic cells that prime CD8+ T cells. For researchers and clinicians interested in tumour immunotherapy, innate adjuvants and combination strategies, this paper points to a promising intratumoural/adjuvant approach. It also flags safety considerations because ALPK1 variants cause autoinflammatory disease and because strong innate activation can harm T cells if not well controlled. The provided datasets and rigorous mechanistic experiments add confidence in the findings and help guide translational assessment.

Why should I read this?

Short version: if you care about turning cold tumours hot or novel innate‑immune ways to boost checkpoint therapies, this is proper must-see stuff. The authors found a trick — tweak a bacterial sugar to make a stable ALPK1 agonist — and it lights up tumours and teams up with PD‑1/CTLA‑4 blockade. It’s clever chemistry + solid immunology and could matter for next‑gen intratumoural therapies. Also, they supply RNA‑seq and pharmacokinetic data so you don’t have to hunt for the details yourself.

Source

Source: https://www.nature.com/articles/s41586-025-09828-9

Data availability (brief)

scRNA-seq and RNA-seq datasets are available via GEO (accessions cited in the paper). Supplementary information and source data are provided with the article.

Author style

Punchy: experimental breadth and translational signalling make this study high‑impact for tumour immunotherapy developers; read the methods and extended data if you are thinking about translating ALPK1 agonists or combining them with checkpoint blockade.