The response rate to PD-1/PD-L1 immune checkpoint inhibition (ICI) therapy in melanoma remains low due to the immunosuppressive tumor microenvironment. Novel strategies synergizing ICI treatment are urgently sought after. Activation of the stimulator of interferon genes (STING) has recently emerged as a critical pathway to overcome immunosuppression. Herein, 2′3′ cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), a universal STING agonist, was encapsulated into lipid nanoparticles conjugated with mannose (LP-cGAMP) for dendritic cell (DC)-specific cytosolic delivery. LP-cGAMP induced STING-related pro-inflammatory and intratumoral injections of LP-cGAMP increased DC maturation and CD8⁺ T cell infiltration more efficiently compared to free cGAMP. Given the upregulation of PD-L1 on tumor cells in response to STING activation, we further tested the combination therapy of LP-cGAMP and anti-PD-L1 and observed a superior antitumor effect in B16F10 and BRAF-mutated murine melanoma models. Our findings prove that targeted delivery of cGAMP can synergize PD-L1 blockade therapy in melanoma and the combinational immune therapy has a great potential to produce a long-lasting anti-tumor effect.

中文翻译：

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脂质平台可增强STING激动剂的活性，从而协同针对黑素瘤的检查站封锁疗法

由于免疫抑制性肿瘤微环境，黑色素瘤对PD-1 / PD-L1免疫检查点抑制（ICI）治疗的应答​​率仍然很低。迫切需要使ICI治疗增效的新策略。干扰素基因刺激物（STING）的激活最近已成为克服免疫抑制的关键途径。在此，将2'3'环状鸟苷单磷酸-腺苷单磷酸（cGAMP）（一种通用的STING激动剂）封装到与甘露糖（LP-cGAMP）缀合的脂质纳米颗粒中，以用于树突状细胞（DC）特异性细胞质递送。LP-cGAMP诱导的STING相关的促炎性和肿瘤内注射LP-cGAMP可增加DC成熟和CD8 ⁺与游离cGAMP相比，T细胞浸润更有效。考虑到PD-L1对STING激活产生的肿瘤细胞上调，我们进一步测试了LP-cGAMP和抗PD-L1的联合治疗，并在B16F10和BRAF突变的小鼠黑色素瘤模型中观察到了优异的抗肿瘤作用。我们的发现证明，cGAMP的靶向递送可以协同黑色素瘤中的PD-L1阻断疗法，并且联合免疫疗法具有产生持久抗肿瘤作用的巨大潜力。