Targeting ARF6-SUCNR1 Axis: Antisense Oligonucleotide Adjuvants for Neutrophil Immunometabolism

Conventional vaccine adjuvants often lack cell-type specificity and readily trigger excessive systemic inflammation, limiting their clinical application. Immunometabolic signaling centered on the ARF6 (ADP-ribosylation factor 6)-SUCNR1 (Succinate receptor 1) axis governs neutrophil recruitment and subsequent B-cell activation at vaccination sites, offering a promising target to balance adjuvant potency and biosafety. Separately published single-gene data confirm two opposing functions for the two mediators: ARF6 overactivation amplifies local pathological inflammation, whereas succinate-stimulated SUCNR1 drives neutrophil infiltration and humoral immune priming. However, direct paired evidence verifying their bidirectional crosstalk within immunization microenvironments remains limited. This review systematically integrates current research on ARF6 and SUCNR1 immunometabolism to outline a hypothetical dual-regulatory adjuvant strategy: local, transient partial silencing of pathological ARF6 activity via ARF6-targeted ASOs (antisense oligonucleotides) paired with localized succinate delivery to sustain protective SUCNR1 signaling. We summarize the molecular basis of this “one inhibition, one activation” paradigm, alongside ASO chemical modification, myeloid-targeted design, and nanocarrier delivery solutions that resolve the unique ARF6 endocytosis paradox. We further dissect unresolved translational risks, including concentration-dependent succinate inflammatory effects, carrier immunogenicity, and potential impairment of baseline neutrophil migration upon ARF6 suppression. Overall, this work synthesizes fragmented mechanistic data to construct a testable neutrophil-centered adjuvant framework, and highlights outstanding technical and biosafety hurdles that require dedicated preclinical validation to support future adjuvant development.