CD8⁺ T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an interaction acts like brakes to prevent T cell overreaction under normal conditions but is exploited by tumor cells to escape the immune surveillance. Immune checkpoint inhibitors have revolutionized cancer therapeutics by removing such brakes. Unfortunately, only a minority of cancer patients respond to immunotherapies presumably due to inadequate immunity. Antitumor immunity depends on the activation of the cGAS-STING pathway, as STING-deficient mice fail to stimulate tumor-infiltrating dendritic cells (DCs) to activate CD8⁺ T cells. STING agonists also enhance natural killer (NK) cells to mediate the clearance of CD8⁺ T cell-resistant tumors. Therefore STING agonists have been intensively sought after. We previously discovered that manganese (Mn) is indispensable for the host defense against cytosolic dsDNA by activating cGAS-STING. Here we report that Mn is also essential in innate immune sensing of tumors and enhances adaptive immune responses against tumors. Mn-insufficient mice had significantly enhanced tumor growth and metastasis, with greatly reduced tumor-infiltrating CD8⁺ T cells. Mechanically, Mn²⁺ promoted DC and macrophage maturation and tumor-specific antigen presentation, augmented CD8⁺ T cell differentiation, activation and NK cell activation, and increased memory CD8⁺ T cells. Combining Mn²⁺ with immune checkpoint inhibition synergistically boosted antitumor efficacies and reduced the anti-PD-1 antibody dosage required in mice. Importantly, a completed phase 1 clinical trial with the combined regimen of Mn²⁺ and anti-PD-1 antibody showed promising efficacy, exhibiting type I IFN induction, manageable safety and revived responses to immunotherapy in most patients with advanced metastatic solid tumors. We propose that this combination strategy warrants further clinical translation.

CD8 ⁺ T 细胞介导的癌症清除通常受到抑制分子（如 PD-1 和 PD-L1）之间的相互作用的抑制，这种相互作用就像刹车一样可以防止 T 细胞在正常条件下过度反应，但被肿瘤细胞利用以逃避免疫监视. 免疫检查点抑制剂通过消除这种刹车彻底改变了癌症治疗方法。不幸的是，大概是由于免疫力不足，只有少数癌症患者对免疫疗法有反应。抗肿瘤免疫依赖于 cGAS-STING 通路的激活，因为 STING 缺陷小鼠不能刺激肿瘤浸润树突状细胞 (DC) 来激活 CD8 ⁺ T 细胞。STING 激动剂还增强自然杀伤 (NK) 细胞以介导 CD8 ^+的清除T细胞抗性肿瘤。因此，STING 激动剂一直备受追捧。我们之前发现锰 (Mn) 通过激活 cGAS-STING 对宿主防御细胞溶质 dsDNA 是必不可少的。在这里，我们报告锰在肿瘤的先天免疫感知中也是必不可少的，并增强了对肿瘤的适应性免疫反应。Mn 不足的小鼠显着增强了肿瘤的生长和转移，肿瘤浸润性 CD8 ⁺ T 细胞大大减少。机械地，Mn ²⁺促进 DC 和巨噬细胞成熟和肿瘤特异性抗原呈递，增强 CD8 ⁺ T 细胞分化、活化和 NK 细胞活化，并增加记忆 CD8 ⁺ T 细胞。结合Mn ²⁺免疫检查点抑制协同提高了抗肿瘤功效并减少了小鼠所需的抗 PD-1 抗体剂量。^{重要的是，一项已完成的 Mn 2+}和抗 PD-1 抗体联合方案的 1 期临床试验显示出有希望的疗效，在大多数晚期转移性实体瘤患者中表现出 I 型 IFN 诱导、可控的安全性和对免疫治疗的恢复反应。我们建议这种组合策略需要进一步的临床转化。