Development and Validation of a Manganese-metabolism and Immune-integrated Gene Signature for Prognosis and Immune Contexture in Patients with Colorectal Cancer
Abstract
Colorectal cancer (CRC) is the third most frequently diagnosed cancer and the second leading cause of cancer-related mortality globally. Emerging evidence identifies manganese as an important trigger for the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, but prognostic signatures integrating manganese metabolism and immune pathways remain unexplored in CRC.
Through analysis of transcriptomic and clinical data from TCGA-CRC and GSE17538 cohorts, we established and validated an eleven-gene manganese metabolism and immune-related signature that robustly stratified CRC patients into distinct risk groups with significant survival differences.
High-risk patients exhibited suppressed immune microenvironments with enriched M2 macrophages and Tregs and activation of oncogenic pathways. Quantitative real-time polymerase chain reaction (qRT-PCR) validation confirmed dysregulation of eight signature genes in clinical CRC samples, indicating the model’s potential for prognostic prediction and immunotherapeutic stratification.
We established a novel MIRGs signature that accurately predicts CRC clinical outcome. Integration of manganese-based agents with immune checkpoint inhibitors (ICIs) represents a potential therapeutic strategy for immunotherapy-resistant CRC.
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25. Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20(1):131.
26. Chen S, Saeed A, Liu Q, Jiang Q, Xu H, Xiao GG, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Tar. 2023;8(1):207.
27. Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13(1):156.
28. Liu X, Wang X, Yang Q, Luo L, Liu Z, Ren X, et al. Th17 Cells Secrete TWEAK to Trigger Epithelial-Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis. Cancer Res. 2024;84(8):1352-71.
29. Yang PS, Yu MH, Hou YC, Chang CP, Lin SC, Kuo IY, et al. Targeting protumor factor chitinase-3-like-1 secreted by Rab37 vesicles for cancer immunotherapy. Theranostics. 2022;12(1):340-61.
30. Hong SM, Lee AY, Kim BJ, Lee JE, Seon SY, Ha YJ, et al. NAMPT-Driven M2 Polarization of Tumor-Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer. Adv Sci. 2024;11(14):e2303177.
31. Zhang Y, Yang Y, Qi X, Cui P, Kang Y, Liu H, et al. SLC14A1 and TGF-beta signaling: a feedback loop driving EMT and colorectal cancer metachronous liver metastasis. J Exp Clin Canc Res. 2024;43(1):208.
32. Song A, Liu B, Li W, Chen B, Gui P, Zhang H, et al. Competitive binding between DDX21 and SIRT7 enhances NAT10-mediated ac(4)C modification to promote colorectal cancer metastasis and angiogenesis- DDX21 promotes colorectal cancer metastasis. Cell Death Dis. 2025;16(1):353.
33. Huang J, Gong Q, Li Q, Xiao M, Li M, Zhang S, et al. Analysis of the immune microenvironment in colorectal cancer with different KRAS gene subtypes. Bmc Cancer. 2025;25(1):1267.
34. Ruiz-Saenz A, Atreya CE, Wang C, Pan B, Dreyer CA, Brunen D, et al. A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAF(V600E) colorectal tumors. Nat Cancer. 2023;4(2):240-56.
35. Han X, Leng C, Zhao S, Wang S, Chen S, Wang S, et al. Development and verification of a manganese metabolism- and immune-related genes signature for prediction of prognosis and immune landscape in gastric cancer. Front Immunol. 2024;15:1377472.
36. Liu Y, Ye H, Zhang R, Liu X, Liu R. A manganese metabolism-related gene signature stratifies prognosis and immunotherapy efficacy in kidney cancer. Discov Oncol. 2025;16(1):1242.
2. Wagle NS, Nogueira L, Devasia TP, Mariotto AB, Yabroff KR, Islami F, et al. Cancer treatment and survivorship statistics, 2025. Ca-Cancer J Clin. 2025;75(4):308-40.
3. Weng J, Li S, Zhu Z, Liu Q, Zhang R, Yang Y, et al. Exploring immunotherapy in colorectal cancer. J Hematol Oncol. 2022;15(1):95.
4. Shin AE, Giancotti FG, Rustgi AK. Metastatic colorectal cancer: mechanisms and emerging therapeutics. Trends Pharmacol Sci. 2023;44(4):222-36.
5. Li J, Wu C, Hu H, Qin G, Wu X, Bai F, et al. Remodeling of the immune and stromal cell compartment by PD-1 blockade in mismatch repair-deficient colorectal cancer. Cancer Cell. 2023;41(6):1152-69.
6. Wang X, Fang Y, Liang W, Wong CC, Qin H, Gao Y, et al. Fusobacterium nucleatum facilitates anti-PD-1 therapy in microsatellite stable colorectal cancer. Cancer Cell. 2024;42(10):1729-46.
7. Andre T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, et al. Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer. New Engl J Med. 2020;383(23):2207-18.
8. Kwon J, Bakhoum SF. The Cytosolic DNA-Sensing cGAS-STING Pathway in Cancer. Cancer Discov. 2020;10(1):26-39.
9. Zhang Z, Zhang C. Regulation of cGAS-STING signalling and its diversity of cellular outcomes. Nat Rev Immunol. 2025;25(6):425-44.
10. Lv M, Chen M, Zhang R, Zhang W, Wang C, Zhang Y, et al. Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy. Cell Res. 2020;30(11):966-79.
11. Wang Y, Wu M, Wang X, Wang P, Ning Z, Zeng Y, et al. Biodegradable MnO(2)-based gene-engineered nanocomposites for chemodynamic therapy and enhanced antitumor immunity. Mater Today Bio. 2023;18:100531.
12. Zhang K, Qi C, Cai K. Manganese-Based Tumor Immunotherapy. Adv Mater. 2023;35(19):e2205409.
13. Wang Y, Fan N, Wang R, Li X, Zhao F, Miao L, et al. Discovery of Airway-Administered Ionophores for Mn(2+) to Mitigate Lung Metastasis by Targeting Disseminated Tumor Cell. Acs Nano. 2025;19(14):14330-50.
14. Peng Y, Liang S, Liu D, Ma K, Yun K, Zhou M, et al. Multi-Metallic Nanosheets Reshaping Immunosuppressive Tumor Microenvironment through Augmenting cGAS-STING Innate Activation and Adaptive Immune Responses for Cancer Immunotherapy. Adv Sci. 2024;11(38):e2403347.
15. Fu Y, Liu S, Zeng S, Shen H. From bench to bed: the tumor immune microenvironment and current immunotherapeutic strategies for hepatocellular carcinoma. J Exp Clin Canc Res. 2019;38(1):396.
16. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat Rev Drug Discov. 2019;18(3):197-218.
17. Feng X, Zahed H, Onwuka J, Callister M, Johansson M, Etzioni R, et al. Cancer Stage Compared With Mortality as End Points in Randomized Clinical Trials of Cancer Screening: A Systematic Review and Meta-Analysis. Jama-J Am Med Assoc. 2024;331(22):1910-7.
18. Fan A, Wang B, Wang X, Nie Y, Fan D, Zhao X, et al. Immunotherapy in colorectal cancer: current achievements and future perspective. Int J Biol Sci. 2021;17(14):3837-49.
19. Yang N, Sun S, Xu J, Gong F, Lei H, Hao Y, et al. Manganese Galvanic Cells Intervene in Tumor Metabolism to Reinforce cGAS-STING Activation for Bidirectional Synergistic Hydrogen-Immunotherapy. Adv Mater. 2025;37(8):e2414929.
20. Liang Q, Chen J, Hou S, Li D, Zhu Y, Li R, et al. Activatable Mn(2+)-Armed nanoagonist augments antitumor immunity in colorectal cancer: A NIR-II Photonic neoadjuvant paradigm. Biomaterials. 2023;300:122206.
21. Ngo U, Shi Y, Woodruff P, Shokat K, DeGrado W, Jo H, et al. IL-13 and IL-17A activate beta1 integrin through an NF-kB/Rho kinase/PIP5K1gamma pathway to enhance force transmission in airway smooth muscle. P Natl Acad Sci Usa. 2024;121(34):e1893716175.
22. Neeli I, Moarefian M, Kuseladass J, Dwivedi N, Jones C, Radic M. Neutrophil attachment via Mac-1 (alpha(M)beta(2); CD11b/CD18; CR3) integrins induces PAD4 deimination of profilin and histone H3. Philos T R Soc B. 2023;378(1890):20220247.
23. Chow A, Perica K, Klebanoff CA, Wolchok JD. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol. 2022;19(12):775-90.
24. Ambrosini M, Rousseau B, Manca P, Artz O, Marabelle A, Andre T, et al. Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer. Ann Oncol. 2024;35(7):643-55.
25. Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20(1):131.
26. Chen S, Saeed A, Liu Q, Jiang Q, Xu H, Xiao GG, et al. Macrophages in immunoregulation and therapeutics. Signal Transduct Tar. 2023;8(1):207.
27. Zhao S, Mi Y, Guan B, Zheng B, Wei P, Gu Y, et al. Tumor-derived exosomal miR-934 induces macrophage M2 polarization to promote liver metastasis of colorectal cancer. J Hematol Oncol. 2020;13(1):156.
28. Liu X, Wang X, Yang Q, Luo L, Liu Z, Ren X, et al. Th17 Cells Secrete TWEAK to Trigger Epithelial-Mesenchymal Transition and Promote Colorectal Cancer Liver Metastasis. Cancer Res. 2024;84(8):1352-71.
29. Yang PS, Yu MH, Hou YC, Chang CP, Lin SC, Kuo IY, et al. Targeting protumor factor chitinase-3-like-1 secreted by Rab37 vesicles for cancer immunotherapy. Theranostics. 2022;12(1):340-61.
30. Hong SM, Lee AY, Kim BJ, Lee JE, Seon SY, Ha YJ, et al. NAMPT-Driven M2 Polarization of Tumor-Associated Macrophages Leads to an Immunosuppressive Microenvironment in Colorectal Cancer. Adv Sci. 2024;11(14):e2303177.
31. Zhang Y, Yang Y, Qi X, Cui P, Kang Y, Liu H, et al. SLC14A1 and TGF-beta signaling: a feedback loop driving EMT and colorectal cancer metachronous liver metastasis. J Exp Clin Canc Res. 2024;43(1):208.
32. Song A, Liu B, Li W, Chen B, Gui P, Zhang H, et al. Competitive binding between DDX21 and SIRT7 enhances NAT10-mediated ac(4)C modification to promote colorectal cancer metastasis and angiogenesis- DDX21 promotes colorectal cancer metastasis. Cell Death Dis. 2025;16(1):353.
33. Huang J, Gong Q, Li Q, Xiao M, Li M, Zhang S, et al. Analysis of the immune microenvironment in colorectal cancer with different KRAS gene subtypes. Bmc Cancer. 2025;25(1):1267.
34. Ruiz-Saenz A, Atreya CE, Wang C, Pan B, Dreyer CA, Brunen D, et al. A reversible SRC-relayed COX2 inflammatory program drives resistance to BRAF and EGFR inhibition in BRAF(V600E) colorectal tumors. Nat Cancer. 2023;4(2):240-56.
35. Han X, Leng C, Zhao S, Wang S, Chen S, Wang S, et al. Development and verification of a manganese metabolism- and immune-related genes signature for prediction of prognosis and immune landscape in gastric cancer. Front Immunol. 2024;15:1377472.
36. Liu Y, Ye H, Zhang R, Liu X, Liu R. A manganese metabolism-related gene signature stratifies prognosis and immunotherapy efficacy in kidney cancer. Discov Oncol. 2025;16(1):1242.
| Files | ||
| Issue | Vol 25 No 1 (2026) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijaai.v25i1.20442 | |
| Keywords | ||
| Colorectal cancer Immunotherapy resistance Manganese metabolism Prognosis | ||
| Rights and permissions | |
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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
He L, Chen Z, Zhang C, Zhu P, Dai S. Development and Validation of a Manganese-metabolism and Immune-integrated Gene Signature for Prognosis and Immune Contexture in Patients with Colorectal Cancer. Iran J Allergy Asthma Immunol. 2026;25(1):93-107.
