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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.