Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

Cell Res. 2020 Nov;30(11):966-979. doi: 10.1038/s41422-020-00395-4. Epub 2020 Aug 24.


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.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Pharmaceutic / pharmacology
  • Adult
  • Aged
  • Animals
  • Antigen Presentation / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology
  • Dendritic Cells / drug effects
  • Drug Resistance, Multiple / drug effects
  • Drug Resistance, Neoplasm / drug effects
  • Female
  • Humans
  • Immunity / drug effects*
  • Immunotherapy*
  • Interferon Type I / metabolism
  • Killer Cells, Natural / immunology
  • Lung / pathology
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Manganese / pharmacology*
  • Melanoma, Experimental / immunology
  • Melanoma, Experimental / pathology
  • Melanoma, Experimental / therapy
  • Membrane Proteins / metabolism*
  • Mice, Inbred C57BL
  • Middle Aged
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Nucleotidyltransferases / metabolism*
  • Organ Size / drug effects
  • Signal Transduction / drug effects
  • Treatment Outcome
  • Tumor Burden / drug effects


  • Adjuvants, Pharmaceutic
  • Interferon Type I
  • Membrane Proteins
  • Sting1 protein, mouse
  • Manganese
  • Nucleotidyltransferases
  • cGAS protein, mouse