Stimulator of interferon genes (STING) agonists rapidly moved into clinical trials with great optimism but have only shown mediocre therapeutic efficacy in patients. Li and colleagues revealed that STING activation in B cells drives immunosuppression that counteracts the stimulatory activity of these drugs, and that blocking regulatory B-cell function can improve STING-based cancer immunotherapy. Using specific deletion of STING (TMEM173) in B cells, they first showed that systemic delivery of STING agonists is more effective in controlling multiple cancer models, most importantly pancreatic ductal adenocarcinomas (PDAC). Next, they found that in response to STING activation, B cells take on a regulatory phenotype and produce two suppressive cytokines, IL35 and IL10. They found that IL35 production is essential for their suppressive nature, acting to suppress natural killer (NK) cell antitumor responses specifically in response to STING agonists. Finally, they showed that a combination of blocking anti-IL35 antibodies in combination...

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