{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:19:27Z","timestamp":1788239967587,"version":"build-2803163510"},"reference-count":74,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:00:00Z","timestamp":1784764800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":39,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Cold tumors remain a major challenge in cancer immunotherapy because of insufficient immune cell infiltration and limited inflammatory signaling, resulting in poor responses to immune checkpoint inhibitors. However, accumulating evidence suggests that many cold tumors are not completely immunologically inert but instead persist in a low-level immune state that fails to sustain effective immune amplification. Based on this perspective, we propose that cold tumors can be more appropriately understood as a threshold-constrained immune state, in which antitumor immune responses have been initiated but remain unable to surpass the immune activation threshold required to establish sustained immune amplification. Within this conceptual framework, we further propose a hierarchical model of immune dysfunction consisting of priming failure, trafficking failure, and penetration failure to explain the systemic mechanisms underlying immune resistance in cold tumors. Building upon this framework, we introduce the Ferroptosis\u2013cGAS\u2013STING amplification circuit as a conceptual model for driving immune state transition. In this model, ferroptosis activates the cGAS\u2013STING\u2013type I interferon axis through the release of tumor antigens and DNA-derived danger signals, whereas STING signaling, in turn, enhances cellular susceptibility to ferroptosis, thereby forming a transient amplification module constrained by temporal and metabolic conditions. This amplification module may enable subthreshold immune responses to overcome the immune activation threshold, thereby creating conditions for subsequent immune amplification while coordinately improving immune priming, immune cell recruitment, and tumor penetration, ultimately alleviating hierarchical immune barriers. Furthermore, we define the functional reprogramming of the tumor\u2013immune system driven by crossing the immune activation threshold as immune setpoint resetting. We also discuss the key regulatory determinants and biological boundaries of this conceptual framework, including the temporal window of amplification, signal intensity, spatial constraints, and functional heterogeneity across different tumor contexts, together with its current limitations and future research directions. Overall, this review establishes a unified conceptual framework linking ferroptosis, innate immune activation, and immune remodeling in cold tumors, providing a systems-level perspective for understanding immune state transition and a theoretical foundation for designing immune interventions based on threshold crossing.<\/jats:p>","DOI":"10.1186\/s12967-026-08683-0","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T10:29:48Z","timestamp":1784802588000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Resetting the immune setpoint of cold tumors through a ferroptosis\u2013cGAS\u2013STING amplification circuit"],"prefix":"10.1186","volume":"24","author":[{"given":"Yi","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinru","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yixin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pengna","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4430-7798","authenticated-orcid":false,"given":"Yuguang","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,23]]},"reference":[{"issue":"6230","key":"8683_CR1","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1126\/science.aaa8172","volume":"348","author":"P Sharma","year":"2015","unstructured":"Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348(6230):56\u201361.","journal-title":"Science"},{"issue":"10304","key":"8683_CR2","doi-asserted-by":"publisher","first-page":"1002","DOI":"10.1016\/S0140-6736(21)01206-X","volume":"398","author":"MS Carlino","year":"2021","unstructured":"Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet. 2021;398(10304):1002\u201314.","journal-title":"Lancet"},{"issue":"8","key":"8683_CR3","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1016\/j.medj.2024.04.011","volume":"5","author":"J Zhao","year":"2024","unstructured":"Zhao J, Wang L, Zhou A, Wen S, Fang W, Zhang L, et al. Decision model for durable clinical benefit from front- or late-line immunotherapy alone or with chemotherapy in non-small cell lung cancer. Med. 2024;5(8):981\u2013e974.","journal-title":"Med"},{"issue":"1","key":"8683_CR4","doi-asserted-by":"publisher","first-page":"118","DOI":"10.1016\/j.eururo.2025.01.021","volume":"88","author":"H Zhang","year":"2025","unstructured":"Zhang H, Liu Y, Lin A, Wang L, Jiang A, Re. Immunogenomic Determinants of Exceptional Response to Immune Checkpoint Inhibition in Renal Cell Carcinoma. Eur Urol. 2025;88(1):118\u20139.","journal-title":"Eur Urol"},{"issue":"1","key":"8683_CR5","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1186\/s40164-024-00543-1","volume":"13","author":"S Zheng","year":"2024","unstructured":"Zheng S, Wang W, Shen L, Yao Y, Xia W, Ni C. Tumor battlefield within inflamed, excluded or desert immune phenotypes: the mechanisms and strategies. Exp Hematol Oncol. 2024;13(1):80.","journal-title":"Exp Hematol Oncol"},{"issue":"1","key":"8683_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.immuni.2013.07.012","volume":"39","author":"DS Chen","year":"2013","unstructured":"Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1\u201310.","journal-title":"Immunity"},{"issue":"3","key":"8683_CR7","doi-asserted-by":"publisher","first-page":"166","DOI":"10.1038\/nri3607","volume":"14","author":"IK Poon","year":"2014","unstructured":"Poon IK, Lucas CD, Rossi AG, Ravichandran KS. Apoptotic cell clearance: basic biology and therapeutic potential. Nat Rev Immunol. 2014;14(3):166\u201380.","journal-title":"Nat Rev Immunol"},{"issue":"5","key":"8683_CR8","doi-asserted-by":"publisher","first-page":"1106","DOI":"10.1038\/s41423-020-00630-3","volume":"18","author":"D Bertheloot","year":"2021","unstructured":"Bertheloot D, Latz E, Franklin BS. Necroptosis, pyroptosis and apoptosis: an intricate game of cell death. Cell Mol Immunol. 2021;18(5):1106\u201321.","journal-title":"Cell Mol Immunol"},{"issue":"2","key":"8683_CR9","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1038\/s41422-020-00441-1","volume":"31","author":"D Tang","year":"2021","unstructured":"Tang D, Chen X, Kang R, Kroemer G. Ferroptosis: molecular mechanisms and health implications. Cell Res. 2021;31(2):107\u201325.","journal-title":"Cell Res"},{"issue":"7237","key":"8683_CR10","doi-asserted-by":"publisher","first-page":"509","DOI":"10.1038\/nature07710","volume":"458","author":"T Fernandes-Alnemri","year":"2009","unstructured":"Fernandes-Alnemri T, Yu JW, Datta P, Wu J, Alnemri ES. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458(7237):509\u201313.","journal-title":"Nature"},{"issue":"1","key":"8683_CR11","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1016\/j.cytogfr.2007.10.006","volume":"19","author":"P Fitzgerald-Bocarsly","year":"2008","unstructured":"Fitzgerald-Bocarsly P, Dai J, Singh S. Plasmacytoid dendritic cells and type I IFN: 50 years of convergent history. Cytokine Growth Factor Rev. 2008;19(1):3\u201319.","journal-title":"Cytokine Growth Factor Rev"},{"issue":"10","key":"8683_CR12","doi-asserted-by":"publisher","first-page":"1142","DOI":"10.1038\/ni.3558","volume":"17","author":"Q Chen","year":"2016","unstructured":"Chen Q, Sun L, Chen ZJ. Regulation and function of the cGAS-STING pathway of cytosolic DNA sensing. Nat Immunol. 2016;17(10):1142\u20139.","journal-title":"Nat Immunol"},{"issue":"7637","key":"8683_CR13","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1038\/nature21349","volume":"541","author":"DS Chen","year":"2017","unstructured":"Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541(7637):321\u201330.","journal-title":"Nature"},{"issue":"7822","key":"8683_CR14","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1038\/s41586-020-2611-3","volume":"584","author":"ST Ferris","year":"2020","unstructured":"Ferris ST, Durai V, Wu R, Theisen DJ, Ward JP, Bern MD, et al. cDC1 prime and are licensed by CD4(+) T cells to induce anti-tumour immunity. Nature. 2020;584(7822):624\u20139.","journal-title":"Nature"},{"issue":"5904","key":"8683_CR15","doi-asserted-by":"publisher","first-page":"1097","DOI":"10.1126\/science.1164206","volume":"322","author":"K Hildner","year":"2008","unstructured":"Hildner K, Edelson BT, Purtha WE, Diamond M, Matsushita H, Kohyama M, et al. Batf3 deficiency reveals a critical role for CD8alpha+ dendritic cells in cytotoxic T cell immunity. Science. 2008;322(5904):1097\u2013100.","journal-title":"Science"},{"issue":"5","key":"8683_CR16","doi-asserted-by":"publisher","first-page":"711","DOI":"10.1016\/j.ccell.2017.04.003","volume":"31","author":"S Spranger","year":"2017","unstructured":"Spranger S, Dai D, Horton B, Gajewski TF. Tumor-Residing Batf3 Dendritic Cells Are Required for Effector T Cell Trafficking and Adoptive T Cell Therapy. Cancer Cell. 2017;31(5):711\u2013e234.","journal-title":"Cancer Cell"},{"key":"8683_CR17","doi-asserted-by":"publisher","first-page":"7458","DOI":"10.1038\/ncomms8458","volume":"6","author":"ME Mikucki","year":"2015","unstructured":"Mikucki ME, Fisher DT, Matsuzaki J, Skitzki JJ, Gaulin NB, Muhitch JB, et al. Non-redundant requirement for CXCR3 signalling during tumoricidal T-cell trafficking across tumour vascular checkpoints. Nat Commun. 2015;6:7458.","journal-title":"Nat Commun"},{"issue":"7693","key":"8683_CR18","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/nature25501","volume":"554","author":"S Mariathasan","year":"2018","unstructured":"Mariathasan S, Turley SJ, Nickles D, Castiglioni A, Yuen K, Wang Y, et al. TGF\u03b2 attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells. Nature. 2018;554(7693):544\u20138.","journal-title":"Nature"},{"issue":"10","key":"8683_CR19","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/s41568-024-00740-4","volume":"24","author":"L Arpinati","year":"2024","unstructured":"Arpinati L, Carradori G, Scherz-Shouval R. CAF-induced physical constraints controlling T cell state and localization in solid tumours. Nat Rev Cancer. 2024;24(10):676\u201393.","journal-title":"Nat Rev Cancer"},{"issue":"11","key":"8683_CR20","doi-asserted-by":"publisher","first-page":"831","DOI":"10.1038\/s41577-025-01187-w","volume":"25","author":"E Lanitis","year":"2025","unstructured":"Lanitis E, Irving M, Coukos G. Tumour-associated vasculature in T cell homing and immunity: opportunities for cancer therapy. Nat Rev Immunol. 2025;25(11):831\u201346.","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"8683_CR21","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1038\/s41392-024-01979-x","volume":"9","author":"B Wu","year":"2024","unstructured":"Wu B, Zhang B, Li B, Wu H, Jiang M. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct Target Ther. 2024;9(1):274.","journal-title":"Signal Transduct Target Ther"},{"issue":"11","key":"8683_CR22","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1038\/s41419-023-06284-z","volume":"14","author":"Y Dondelinger","year":"2023","unstructured":"Dondelinger Y, Priem D, Huyghe J, Delanghe T, Vandenabeele P, Bertrand MJM. NINJ1 is activated by cell swelling to regulate plasma membrane permeabilization during regulated necrosis. Cell Death Dis. 2023;14(11):755.","journal-title":"Cell Death Dis"},{"issue":"9","key":"8683_CR23","doi-asserted-by":"publisher","first-page":"1050","DOI":"10.1038\/nm1622","volume":"13","author":"L Apetoh","year":"2007","unstructured":"Apetoh L, Ghiringhelli F, Tesniere A, Obeid M, Ortiz C, Criollo A, et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat Med. 2007;13(9):1050\u20139.","journal-title":"Nat Med"},{"issue":"10","key":"8683_CR24","doi-asserted-by":"publisher","first-page":"1170","DOI":"10.1038\/nm.2028","volume":"15","author":"F Ghiringhelli","year":"2009","unstructured":"Ghiringhelli F, Apetoh L, Tesniere A, Aymeric L, Ma Y, Ortiz C, et al. Activation of the NLRP3 inflammasome in dendritic cells induces IL-1beta-dependent adaptive immunity against tumors. Nat Med. 2009;15(10):1170\u20138.","journal-title":"Nat Med"},{"key":"8683_CR25","doi-asserted-by":"publisher","first-page":"103719","DOI":"10.1016\/j.redox.2025.103719","volume":"85","author":"M Ioannidis","year":"2025","unstructured":"Ioannidis M, Tjepkema J, Uitbeijerse MRP, van den Bogaart G. Immunomodulatory effects of 4-hydroxynonenal. Redox Biol. 2025;85:103719.","journal-title":"Redox Biol"},{"key":"8683_CR26","doi-asserted-by":"publisher","first-page":"117298","DOI":"10.1016\/j.biopha.2024.117298","volume":"179","author":"X Li","year":"2024","unstructured":"Li X, Li Y, Tuerxun H, Zhao Y, Liu X, Zhao Y. Firing up cold tumors: Ferroptosis causes immune activation by improving T cell infiltration. Biomed Pharmacother. 2024;179:117298.","journal-title":"Biomed Pharmacother"},{"issue":"2","key":"8683_CR27","doi-asserted-by":"publisher","first-page":"306","DOI":"10.1016\/j.ccell.2025.12.013","volume":"44","author":"L Li","year":"2026","unstructured":"Li L, Ye Q, Ma J, Wang Z, Liu T, Lei Y, et al. Ubiquitination-directed cytosolic DNA degradation governs cGAS-STING-mediated immune response to DNA damage. Cancer Cell. 2026;44(2):306\u2013. \u2013\u200920.e7.","journal-title":"Cancer Cell"},{"issue":"1","key":"8683_CR28","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.immuni.2020.05.013","volume":"53","author":"X Zhang","year":"2020","unstructured":"Zhang X, Bai XC, Chen ZJ. Structures and Mechanisms in the cGAS-STING Innate Immunity Pathway. Immunity. 2020;53(1):43\u201353.","journal-title":"Immunity"},{"issue":"1","key":"8683_CR29","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1186\/s13045-025-01691-5","volume":"18","author":"M Shen","year":"2025","unstructured":"Shen M, Jiang X, Peng Q, Oyang L, Ren Z, Wang J, et al. The cGAS\u2013STING pathway in cancer immunity: mechanisms, challenges, and therapeutic implications. J Hematol Oncol. 2025;18(1):40.","journal-title":"J Hematol Oncol"},{"issue":"1","key":"8683_CR30","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/cr.2011.1","volume":"21","author":"SC Sun","year":"2011","unstructured":"Sun SC, Liu ZG. A special issue on NF-\u03baB signaling and function. Cell Res. 2011;21(1):1\u20132.","journal-title":"Cell Res"},{"issue":"2","key":"8683_CR31","doi-asserted-by":"publisher","first-page":"260","DOI":"10.1016\/j.ccell.2025.12.002","volume":"44","author":"CG Fahey","year":"2026","unstructured":"Fahey CG, Cordova AF, Gedeon PC, Barbie DA. Targeting STING to generate therapeutic anti-tumor immunity. Cancer Cell. 2026;44(2):260\u201380.","journal-title":"Cancer Cell"},{"issue":"8","key":"8683_CR32","doi-asserted-by":"publisher","first-page":"2076","DOI":"10.1158\/0008-5472.CAN-15-1456","volume":"76","author":"H Lemos","year":"2016","unstructured":"Lemos H, Mohamed E, Huang L, Ou R, Pacholczyk G, Arbab AS, et al. STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation. Cancer Res. 2016;76(8):2076\u201381.","journal-title":"Cancer Res"},{"issue":"3","key":"8683_CR33","doi-asserted-by":"publisher","first-page":"503","DOI":"10.1016\/j.ccell.2025.02.014","volume":"43","author":"H Song","year":"2025","unstructured":"Song H, Chen L, Pan X, Shen Y, Ye M, Wang G, et al. Targeting tumor monocyte-intrinsic PD-L1 by rewiring STING signaling and enhancing STING agonist therapy. Cancer Cell. 2025;43(3):503\u2013e1810.","journal-title":"Cancer Cell"},{"issue":"8","key":"8683_CR34","doi-asserted-by":"publisher","first-page":"519","DOI":"10.1038\/s41419-023-06045-y","volume":"14","author":"Y Liu","year":"2023","unstructured":"Liu Y, Lu S, Wu LL, Yang L, Yang L, Wang J. The diversified role of mitochondria in ferroptosis in cancer. Cell Death Dis. 2023;14(8):519.","journal-title":"Cell Death Dis"},{"issue":"6","key":"8683_CR35","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1038\/s41580-024-00703-5","volume":"25","author":"SJ Dixon","year":"2024","unstructured":"Dixon SJ, Olzmann JA. The cell biology of ferroptosis. Nat Rev Mol Cell Biol. 2024;25(6):424\u201342.","journal-title":"Nat Rev Mol Cell Biol"},{"issue":"1","key":"8683_CR36","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/s41392-025-02253-4","volume":"10","author":"X Xu","year":"2025","unstructured":"Xu X, Pang Y, Fan X. Mitochondria in oxidative stress, inflammation and aging: from mechanisms to therapeutic advances. Signal Transduct Target Ther. 2025;10(1):190.","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"8683_CR37","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1038\/s41420-023-01712-7","volume":"9","author":"HY Li","year":"2023","unstructured":"Li HY, Wei TT, Zhuang M, Tan CY, Xie TH, Cai J, et al. Iron derived from NCOA4-mediated ferritinophagy causes cellular senescence via the cGAS-STING pathway. Cell Death Discov. 2023;9(1):419.","journal-title":"Cell Death Discov"},{"key":"8683_CR38","doi-asserted-by":"publisher","first-page":"65","DOI":"10.1016\/j.jot.2024.03.005","volume":"46","author":"X Jing","year":"2024","unstructured":"Jing X, Wang W, He X, Liu X, Yang X, Su C, et al. HIF-2\u03b1\/TFR1 mediated iron homeostasis disruption aggravates cartilage endplate degeneration through ferroptotic damage and mtDNA release: A new mechanism of intervertebral disc degeneration. J Orthop Translat. 2024;46:65\u201378.","journal-title":"J Orthop Translat"},{"issue":"7","key":"8683_CR39","doi-asserted-by":"publisher","first-page":"727","DOI":"10.1038\/s41590-020-0699-0","volume":"21","author":"M Jia","year":"2020","unstructured":"Jia M, Qin D, Zhao C, Chai L, Yu Z, Wang W, et al. Redox homeostasis maintained by GPX4 facilitates STING activation. Nat Immunol. 2020;21(7):727\u201335.","journal-title":"Nat Immunol"},{"issue":"1\u20132","key":"8683_CR40","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.cell.2013.12.010","volume":"156","author":"WS Yang","year":"2014","unstructured":"Yang WS, SriRamaratnam R, Welsch ME, Shimada K, Skouta R, Viswanathan VS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156(1\u20132):317\u201331.","journal-title":"Cell"},{"issue":"3","key":"8683_CR41","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1038\/s41568-025-00894-9","volume":"26","author":"C Lu","year":"2026","unstructured":"Lu C, Wang W, Fu YX. Opportunities and challenges of targeting cGAS-STING in cancer. Nat Rev Cancer. 2026;26(3):200\u201316.","journal-title":"Nat Rev Cancer"},{"issue":"20","key":"8683_CR42","doi-asserted-by":"publisher","first-page":"3807","DOI":"10.1016\/j.molcel.2025.08.030","volume":"85","author":"A Shim","year":"2025","unstructured":"Shim A, Chen Y, Maciejowski J. Activation and regulation of cGAS-STING signaling in cancer cells. Mol Cell. 2025;85(20):3807\u201322.","journal-title":"Mol Cell"},{"issue":"10","key":"8683_CR43","doi-asserted-by":"publisher","first-page":"3084","DOI":"10.1016\/j.ymthe.2023.07.026","volume":"31","author":"L Gao","year":"2023","unstructured":"Gao L, Zhang J, Yang T, Jiang L, Liu X, Wang S, et al. STING\/ACSL4 axis-dependent ferroptosis and inflammation promote hypertension-associated chronic kidney disease. Mol Ther. 2023;31(10):3084\u2013103.","journal-title":"Mol Ther"},{"issue":"1","key":"8683_CR44","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/nchembio.2238","volume":"13","author":"VE Kagan","year":"2017","unstructured":"Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13(1):81\u201390.","journal-title":"Nat Chem Biol"},{"issue":"24","key":"8683_CR45","doi-asserted-by":"publisher","first-page":"1922","DOI":"10.1038\/s41388-025-03368-2","volume":"44","author":"M Li","year":"2025","unstructured":"Li M, Jin S, Ma H, Yang X, Zhang Z. Reciprocal regulation between ferroptosis and STING-type I interferon pathway suppresses head and neck squamous cell carcinoma growth through dendritic cell maturation. Oncogene. 2025;44(24):1922\u201335.","journal-title":"Oncogene"},{"key":"8683_CR46","doi-asserted-by":"publisher","first-page":"698679","DOI":"10.3389\/fcell.2021.698679","volume":"9","author":"C Li","year":"2021","unstructured":"Li C, Liu J, Hou W, Kang R, Tang D. STING1 Promotes Ferroptosis Through MFN1\/2-Dependent Mitochondrial Fusion. Front Cell Dev Biol. 2021;9:698679.","journal-title":"Front Cell Dev Biol"},{"issue":"3","key":"8683_CR47","doi-asserted-by":"publisher","first-page":"688","DOI":"10.1016\/j.cell.2013.09.049","volume":"155","author":"H Konno","year":"2013","unstructured":"Konno H, Konno K, Barber GN. Cyclic dinucleotides trigger ULK1 (ATG1) phosphorylation of STING to prevent sustained innate immune signaling. Cell. 2013;155(3):688\u201398.","journal-title":"Cell"},{"issue":"5","key":"8683_CR48","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1084\/jem.20180139","volume":"215","author":"T Li","year":"2018","unstructured":"Li T, Chen ZJ. The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. J Exp Med. 2018;215(5):1287\u201399.","journal-title":"J Exp Med"},{"issue":"24","key":"8683_CR49","doi-asserted-by":"publisher","first-page":"3251","DOI":"10.1097\/CM9.0000000000003904","volume":"138","author":"Y Xiao","year":"2025","unstructured":"Xiao Y, Ma Y, Zhao J, Zhang X, Gan C, Gao J, et al. cGAS-STING signaling pathway as a therapeutic target in human diseases. Chin Med J (Engl). 2025;138(24):3251\u201384.","journal-title":"Chin Med J (Engl)"},{"issue":"12","key":"8683_CR50","doi-asserted-by":"publisher","first-page":"760","DOI":"10.1038\/nri3921","volume":"15","author":"GN Barber","year":"2015","unstructured":"Barber GN. STING: infection, inflammation and cancer. Nat Rev Immunol. 2015;15(12):760\u201370.","journal-title":"Nat Rev Immunol"},{"key":"8683_CR51","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1016\/j.jare.2024.12.028","volume":"76","author":"L Ding","year":"2025","unstructured":"Ding L, Zhang R, Du W, Wang Q, Pei D. The role of cGAS-STING signaling pathway in ferroptosis. J Adv Res. 2025;76:219\u201331.","journal-title":"J Adv Res"},{"issue":"6","key":"8683_CR52","doi-asserted-by":"publisher","first-page":"622","DOI":"10.1016\/j.scib.2023.02.027","volume":"68","author":"JL Liang","year":"2023","unstructured":"Liang JL, Jin XK, Zhang SM, Huang QX, Ji P, Deng XC, et al. Specific activation of cGAS-STING pathway by nanotherapeutics-mediated ferroptosis evoked endogenous signaling for boosting systemic tumor immunotherapy. Sci Bull (Beijing). 2023;68(6):622\u201336.","journal-title":"Sci Bull (Beijing)"},{"issue":"2","key":"8683_CR53","doi-asserted-by":"publisher","first-page":"487","DOI":"10.1158\/1078-0432.CCR-19-1868","volume":"26","author":"IG House","year":"2020","unstructured":"House IG, Savas P, Lai J, Chen AXY, Oliver AJ, Teo ZL, et al. Macrophage-Derived CXCL9 and CXCL10 Are Required for Antitumor Immune Responses Following Immune Checkpoint Blockade. Clin Cancer Res. 2020;26(2):487\u2013504.","journal-title":"Clin Cancer Res"},{"issue":"9","key":"8683_CR54","doi-asserted-by":"publisher","first-page":"1774","DOI":"10.1136\/gutjnl-2022-327909","volume":"72","author":"C Conche","year":"2023","unstructured":"Conche C, Finkelmeier F, Pe\u0161i\u0107 M, Nicolas AM, B\u00f6ttger TW, Kennel KB, et al. Combining ferroptosis induction with MDSC blockade renders primary tumours and metastases in liver sensitive to immune checkpoint blockade. Gut. 2023;72(9):1774\u201382.","journal-title":"Gut"},{"issue":"1","key":"8683_CR55","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1038\/s41392-021-00641-0","volume":"6","author":"F Wu","year":"2021","unstructured":"Wu F, Yang J, Liu J, Wang Y, Mu J, Zeng Q, et al. Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer. Signal Transduct Target Ther. 2021;6(1):218.","journal-title":"Signal Transduct Target Ther"},{"issue":"1","key":"8683_CR56","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1038\/s41392-024-01764-w","volume":"9","author":"Z Deng","year":"2024","unstructured":"Deng Z, Fan T, Xiao C, Tian H, Zheng Y, Li C, et al. TGF-\u03b2 signaling in health, disease, and therapeutics. Signal Transduct Target Ther. 2024;9(1):61.","journal-title":"Signal Transduct Target Ther"},{"issue":"6","key":"8683_CR57","doi-asserted-by":"publisher","first-page":"4871","DOI":"10.1021\/jacs.4c13241","volume":"147","author":"H Zhao","year":"2025","unstructured":"Zhao H, Jin S, Liu Y, Wang Q, Tan BSN, Wang S, et al. A Second Near-Infrared Window-Responsive Metal-Organic-Framework-Based Photosensitizer for Tumor Immunotherapy via Synergistic Ferroptosis and STING Activation. J Am Chem Soc. 2025;147(6):4871\u201385.","journal-title":"J Am Chem Soc"},{"issue":"24","key":"8683_CR58","doi-asserted-by":"publisher","first-page":"e2300881","DOI":"10.1002\/advs.202300881","volume":"10","author":"F Jiang","year":"2023","unstructured":"Jiang F, Jia K, Chen Y, Ji C, Chong X, Li Z, et al. ANO1-Mediated Inhibition of Cancer Ferroptosis Confers Immunotherapeutic Resistance through Recruiting Cancer-Associated Fibroblasts. Adv Sci (Weinh). 2023;10(24):e2300881.","journal-title":"Adv Sci (Weinh)"},{"issue":"1","key":"8683_CR59","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/s41420-024-01958-9","volume":"10","author":"C Chen","year":"2024","unstructured":"Chen C, Liu J, Lin X, Xiang A, Ye Q, Guo J, et al. Crosstalk between cancer-associated fibroblasts and regulated cell death in tumors: insights into apoptosis, autophagy, ferroptosis, and pyroptosis. Cell Death Discov. 2024;10(1):189.","journal-title":"Cell Death Discov"},{"key":"8683_CR60","doi-asserted-by":"crossref","unstructured":"Lee SJ, Yang H, Kim WR, Lee YS, Lee WS, Kong SJ, et al. STING activation normalizes the intraperitoneal vascular-immune microenvironment and suppresses peritoneal carcinomatosis of colon cancer. J Immunother Cancer. 2021;9(6).","DOI":"10.1136\/jitc-2020-002195"},{"key":"8683_CR61","doi-asserted-by":"crossref","unstructured":"Zhang H, Wang Z, Wu J, Zheng YQ, Zhao Q, He S, et al. Endothelial STING-JAK1 interaction promotes tumor vasculature normalization and antitumor immunity. J Clin Invest. 2025;135(2).","DOI":"10.1172\/JCI180622"},{"issue":"1","key":"8683_CR62","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1186\/s12943-024-01999-9","volume":"23","author":"J Diao","year":"2024","unstructured":"Diao J, Jia Y, Dai E, Liu J, Kang R, Tang D, et al. Ferroptotic therapy in cancer: benefits, side effects, and risks. Mol Cancer. 2024;23(1):89.","journal-title":"Mol Cancer"},{"issue":"8","key":"8683_CR63","doi-asserted-by":"publisher","first-page":"660","DOI":"10.1038\/s44222-025-00337-y","volume":"3","author":"P Dosta","year":"2025","unstructured":"Dosta P, Cryer AM, Prado M, Artzi N. Bioengineering strategies to optimize STING agonist therapy. Nat Reviews Bioeng. 2025;3(8):660\u201380.","journal-title":"Nat Reviews Bioeng"},{"issue":"4","key":"8683_CR64","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1158\/1078-0432.CCR-21-1963","volume":"28","author":"F Meric-Bernstam","year":"2022","unstructured":"Meric-Bernstam F, Sweis RF, Hodi FS, Messersmith WA, Andtbacka RHI, Ingham M, et al. Phase I Dose-Escalation Trial of MIW815 (ADU-S100), an Intratumoral STING Agonist, in Patients with Advanced\/Metastatic Solid Tumors or Lymphomas. Clin Cancer Res. 2022;28(4):677\u201388.","journal-title":"Clin Cancer Res"},{"issue":"20","key":"8683_CR65","doi-asserted-by":"publisher","first-page":"3874","DOI":"10.1016\/j.molcel.2025.09.007","volume":"85","author":"R Chen","year":"2025","unstructured":"Chen R, Zou J, Liu J, Kang R, Tang D. DAMPs in the immunogenicity of cell death. Mol Cell. 2025;85(20):3874\u201389.","journal-title":"Mol Cell"},{"issue":"6","key":"8683_CR66","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1038\/s41577-024-01112-7","volume":"25","author":"Z Zhang","year":"2025","unstructured":"Zhang Z, Zhang C. Regulation of cGAS-STING signalling and its diversity of cellular outcomes. Nat Rev Immunol. 2025;25(6):425\u201344.","journal-title":"Nat Rev Immunol"},{"issue":"1","key":"8683_CR67","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1186\/s13046-025-03520-6","volume":"44","author":"C Li","year":"2025","unstructured":"Li C, Zhao W, Geng D, Jin Y, Guan W. Targeting the interplay of cGAS-STING and ferroptosis by nanomedicine in the treatment of cancer. J Exp Clin Cancer Res. 2025;44(1):249.","journal-title":"J Exp Clin Cancer Res"},{"issue":"8","key":"8683_CR68","doi-asserted-by":"publisher","first-page":"544","DOI":"10.1038\/s44222-023-00099-5","volume":"1","author":"NE-S Ibrahim","year":"2023","unstructured":"Ibrahim NE-S. Targeted delivery of anti-tumour STING agonist. Nat Reviews Bioeng. 2023;1(8):544.","journal-title":"Nat Reviews Bioeng"},{"key":"8683_CR69","doi-asserted-by":"publisher","first-page":"102749","DOI":"10.1016\/j.nantod.2025.102749","volume":"63","author":"S Guo","year":"2025","unstructured":"Guo S, Guan T, Tai R, Ma L, Ke Y, Ye J, et al. A nuclei bombing nano-system improves STING-activated cancer immunotherapy. Nano Today. 2025;63:102749.","journal-title":"Nano Today"},{"issue":"12","key":"8683_CR70","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1038\/s41568-025-00864-1","volume":"25","author":"A Wahida","year":"2025","unstructured":"Wahida A, Conrad M. Decoding ferroptosis for cancer therapy. Nat Rev Cancer. 2025;25(12):910\u201324.","journal-title":"Nat Rev Cancer"},{"issue":"5","key":"8683_CR71","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1016\/j.ccell.2022.04.009","volume":"40","author":"JT Low","year":"2022","unstructured":"Low JT, Chandramohan V, Bowie ML, Brown MC, Waitkus MS, Briley A, et al. Epigenetic STING silencing is developmentally conserved in gliomas and can be rescued by methyltransferase inhibition. Cancer Cell. 2022;40(5):439\u201340.","journal-title":"Cancer Cell"},{"issue":"8","key":"8683_CR72","doi-asserted-by":"publisher","first-page":"1146","DOI":"10.1038\/s41590-022-01278-z","volume":"23","author":"Reactivity to","year":"2022","unstructured":"Reactivity to. type I interferon is key to predict cancer immunotherapy response. Nat Immunol. 2022;23(8):1146\u20137.","journal-title":"Nat Immunol"},{"issue":"1","key":"8683_CR73","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1038\/s41568-023-00635-w","volume":"24","author":"TR Mempel","year":"2024","unstructured":"Mempel TR, Lill JK, Altenburger LM. How chemokines organize the tumour microenvironment. Nat Rev Cancer. 2024;24(1):28\u201350.","journal-title":"Nat Rev Cancer"},{"issue":"1","key":"8683_CR74","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s12943-024-02023-w","volume":"23","author":"X Lin","year":"2024","unstructured":"Lin X, Kang K, Chen P, Zeng Z, Li G, Xiong W, et al. Regulatory mechanisms of PD-1\/PD-L1 in cancers. Mol Cancer. 2024;23(1):108.","journal-title":"Mol Cancer"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-026-08683-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-08683-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-08683-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T05:02:30Z","timestamp":1788238950000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12967-026-08683-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,23]]},"references-count":74,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8683"],"URL":"https:\/\/doi.org\/10.1186\/s12967-026-08683-0","relation":{},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,23]]},"assertion":[{"value":"13 April 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1122"}}