Institute Investigator Scripps Research La Jolla, California, United States
Disclosure(s):
sunnie Yoh, PhD: No financial relationships to disclose
Introduction/Rationale: Effective activation of antigen-presenting cells (APCs) is essential for durable vaccine responses and successful cancer immunotherapy, yet pharmacologic strategies to achieve it remain limited.
Methods: Approximately 1000 compounds of Library of Pharmacologically Active Compounds (LOPAC) were screened to identify inducers of innate immune responses in activation of monocyte-derived dendritic cells (MDDCs).
Results: We identify cardiac glycosides (CGs) as a class of small-molecule immunopotentiators that trigger a non-canonical STAT1 pathway through the Na⁺/K⁺-ATPase-Src-p38 axis. In primary human dendritic cells, the CGs Bufalin and ouabain induce serine STAT1 phosphorylation (S727) independent of interferon signaling, driving a distinct proinflammatory and antigen-presentation program. Bufalin enhances CD8⁺ T-cell priming in response to mRNA vaccination and, in combination with an oncolytic Newcastle disease virus, promotes myeloid remodeling and enhances tumor regression in vivo.
Conclusion: These findings reveal a previously unrecognized mechanism linking Na⁺/K⁺-ATPase signaling to immune activation through non-canonical STAT1 pathway activation. Identification of non-toxic agonists of this pathway may lead to a next-generation of small-molecule adjuvants and immunotherapy co-agents.
