ALPK1 agonists: a new strategy for cancer immunotherapy

A recent study by Tian et al. 1 in Nature shows that alpha-protein kinase 1 (ALPK1) activation with ADP-glycero--D-manno-heptose (ADP-heptose), and even more potently with the phosphorothioate analog UDSP-heptose, triggers strong immune responses against tumors, leading to tumor regression through a mechanism distinct from Toll-like receptors 7/8 (TLR7/8) or stimulator of interferon genes (STING) agonists yet capable of synergizing with them when combined (Fig. 1).These findings support a novel therapeutic paradigm that positions ALPK1 agonists as promising targets for next-generation immunotherapy.Considered a breakthrough in cancer treatment, immunotherapy, including immune checkpoint inhibitors (ICIs) and adoptive T cell therapies, leverages the immune system to recognize and eliminate cancer cells by attenuating immunosuppressive signals of the tumor microenvironment (TME) and amplifying patient T cell-mediated response.However, patient responses are highly heterogeneous, highlighting the need to enhance antitumor immunity by different means. 2 One approach is targeting the innate immune response, which alters the immune landscape including TME by activating the secretion of interferons, proinflammatory cytokines, and chemokines.Agonists of classical innate immune signaling pathways, such as TLRs and STING, trigger inflammatory cascades that promote immune cell infiltration into tumors and activate adaptive immune responses. 2However, their clinical translation has been hampered by doselimiting toxicity, systemic inflammation, and, particularly in the case of STING agonists, induction of T cell apoptosis and loss of immune durability.Tian et al. 1 now identify the innate immune cytosolic receptor ALPK1 as a potential strategy to overcome these limitations.Engagement of ALPK1 by ADP-heptose triggers activation of the transcription factor nuclear factor kappa-lightchain-enhancer of activated B cells (NF-B). 3It has also been shown that ALPK1 can be activated allosterically by CDP-heptose and UDP-heptose. 4Disease-causing mutations in human ALPK1 show alterations in its specificity for these effectors, leading to aberrant activation by endogenous nucleoside diphosphate (NDP) sugars (GDP-mannose, UDP-mannose, and ADPribose), potentially triggering subliminal inflammation. 5ian et al. 1 showed that administration of ADP-heptose increases proinflammatory chemokines, e.g., CXCL10, CCL2, and CCL4, in mouse and cell culture studies.Additionally, in different mouse tumor models (B16F10-OVA, 4T1-OVA, MC38, and Hepa1-6), intratumoral injections of ADP-heptose inhibited tumor growth significantly.This antitumor effect was absent in Alpk1 -/-mice, indicating that tumor regression is mediated by ALPK1-dependent processes.These data also suggest that tumor cell-intrinsic ALPK1 is not contributing to the observed regression.Building on this therapeutic potential of ALPK1 agonists, different ADP-heptose analogs generated through medicinal chemistry were examined.