Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy
Open accessAbstract
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, Mn 2+ 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 Mn 2+ 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 Mn 2+ 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.
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Preliminary data showed that some combination therapies (ADU-S100 plus spartalizumab, MK-1454 plus pembrolizumab, manganese plus α-PD-1) had encouraging antitumor activity with a tolerable safety profile.
“The preliminary data showed that some combination therapies (e.g. ADU-S100 plus spartalizumab, MK-1454 plus pembrolizumab, manganese plus α-PD-1) had encouraging antitumor activity with a tolerable safety profile [270, 275, 276].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [270]
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- Authors
- Lv, M., Chen, M., Zhang, R., Zhang, W., Wang, C., Zhang, Y., Wei, X., Guan, Y., Liu, J., Feng, K., Jing, M., Wang, X., Liu, Y.-C., Mei, Q., Han, W., & Jiang, Z.
- Affiliations
- Peking University (CN)
- Chinese PLA General Hospital (CN)
- Cornell University (US)
- National Institutes of Health (US)
- Center for Life Sciences (CN)
- Corresponding author
- Mei, Qian
- Han, Weidong
- Jiang, Zhengfan
- ORCID
- Venue
- Cell Research
- Published
- 2020-08-24
- Volume
- 30
- Issue
- 11
- Pages
- 966-979
- ISSN
- 1001-0602 (ISSN-L)
- 1748-7838
- PMC
- PMC7785004
- OpenAlex
- W3080399909
- Cited by
- 1,040
- References
- 81
- Citations by year
- 2026: 190 · 2025: 260 · 2024: 252 · 2023: 154 · 2022: 129 · 2021: 53 · 2020: 1
- FWCI
- 30.88
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- Cell Research (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Greater South Information System
- Funders
- National Natural Science Foundation of China (31830022, 81621001, 81830002, 81773248)
- Ministry of Science and Technology of the People’s Republic of China (2019YFA0508500)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- manganese, cGAS-STING pathway, antitumor immunity, immune checkpoint inhibitors, anti-PD-1 therapy, CD8+ T cells, dendritic cell maturation, macrophage maturation, NK cell activation, tumor-infiltrating lymphocytes, type I interferon, cancer immunotherapy, manganese deficiency, metastatic solid tumors
- MeSH terms
- STING Protein, Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase, Adjuvants, Pharmaceutic, Adult, Aged, Animals, Dendritic Cells, Female, Humans, Immunity, Immunotherapy, Interferon Type I, Killer Cells, Natural, Lung, Lymphocyte Activation, Male, Manganese, Melanoma, Experimental, Membrane Proteins, Mice, Inbred C57BL, Middle Aged, Neoplasms, Nucleotidyltransferases, Organ Size, Signal Transduction, Treatment Outcome, Antigen Presentation, CD8-Positive T-Lymphocytes, Drug Resistance, Multiple, Drug Resistance, Neoplasm, Tumor Burden, Carcinogenesis
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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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