cGAS-STING pathway activation has attracted considerable attention in antitumor immunotherapy, but clinical outcomes lag behind expectations due to overlooked negative feedback mechanisms. Here, we determine that STING activation promotes tumor stemness, which weakens the efficacy of STING-based therapies, presenting a double-edged sword. To address this therapeutic paradox, a simple metal-phenolic polymeric micelle (HMQ) was developed, in which Mn2+ (a STING agonist) is coordinated with quercetin (a stemness inhibitor) and hyaluronic acid (HA), to unlock the full therapeutic potential of the cGAS-STING pathway. This unique coordination structure integrates active targeting with rapid and pH-responsive drug release. Importantly, the released drugs remained in their original form, avoiding potential changes in bioactivity. HMQ effectively mitigates the stemness-promoting effects of STING activation, thus significantly amplifying the potency of cGAS-STING-based therapies. This intelligent and facile HMQ establishes a new generation of cGAS-STING agonists with promising clinical translatability and provides a flexible platform for the win-win strategy.
Keywords: STAT3 inhibitor; antitumor immunotherapy; cGAS-STING pathway; coordination polymeric micelle; tumor stemness.