As prophylactic vaccine adjuvants for infectious diseases, cyclic dinucleotides (CDNs) induce safe, potent, long-lasting humoral and cellular memory responses in the systemic and mucosal compartments. As therapeutic cancer vaccine adjuvants, CDNs induce potent anti-tumor immunity, including cytotoxic T cells and NK cells activation that achieve durable regression in multiple mouse models of tumors. Clinical trials are ongoing to fulfill the promise of CDNs (ClinicalTrials.gov: NCT02675439, NCT03010176, NCT03172936, and NCT03937141). However, in October 2018, the first clinical data with Merck’s CDN MK-1454 showed zero activity as a monotherapy in patients with solid tumors or lymphomas (NCT03010176). Lately, the clinical trial from Aduro’s CDN ADU-S100 monotherapy was also disappointing (NCT03172936). The emerging hurdle in CDN vaccine development calls for a timely re-evaluation of our understanding on CDN vaccine adjuvants. Here, we review the status of CDN vaccine adjuvant research, including their superior adjuvant activities, in vivo mode of action, and confounding factors that affect their efficacy in humans. Lastly, we discuss the strategies to overcome the hurdle and advance promising CDN adjuvants in humans.

Bardet-Biedl syndrome (BBS), a ciliopathy characterized by obesity, hyperphagia, and learning deficits, arises from mutations in Bbs genes. Exacerbated symptoms occur with mutations in genes encoding the BBSome, a complex regulating primary cilia function. We investigated the mechanisms underlying BBS-induced obesity using a Bbs5 -knockout ( Bbs5 ^–/– ) mouse model. Bbs5 ^–/– mice were characterized by hyperphagia, learning deficits, glucose/insulin intolerance, and disrupted metabolic hormones, phenocopying human BBS. White adipose tissue in these mice had a unique immunophenotype, with increased proinflammatory macrophages and dysfunctional Tregs, suggesting a mechanism for adiposity distinct from those of typical obesity models. Additionally, Bbs5 ^–/– mice exhibited pancreatic islet hyperplasia but failed to normalize blood glucose, suggesting defective insulin action. Hypothalamic transcriptomics revealed dysregulation of endocrine signaling pathways, with functional analyses confirming defects in insulin, leptin, and cholecystokinin (CCK) signaling, while glucagon-like peptide-1 receptor (GLP-1R) responsiveness was preserved. Notably, treatment with a GLP-1RA effectively alleviated hyperphagia and body weight gain, improved glucose tolerance, and regulated circulating metabolic hormones in Bbs5 ^–/– mice. This study suggests that Bbs5 ^–/– mice represent a valuable translational model of BBS for understanding pathogenesis and developing better treatments. Our findings highlight the therapeutic potential of GLP-1RAs for managing BBS-associated metabolic dysregulation, indicating that further investigation for clinical application is warranted.