Global cancer burden growing, amidst mounting need for services. Saudi Med J. 2024;45:326–7.
Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49.
Krüger M, Richter P. To die or not to die: cell death in biology and disease. Int J Mol Sci. 2022;23:6734.
Shen S, Shao Y, Li C. Different types of cell death and their shift in shaping disease. Cell Death Discov. 2023;9:284.
Newton K, Strasser A, Kayagaki N, Dixit VM. Cell death. Cell. 2024;187:235–56.
Christgen S, Tweedell RE, Kanneganti TD. Programming inflammatory cell death for therapy. Pharmacol Ther. 2022;232:108010.
Degterev A, Huang Z, Boyce M, Li Y, Jagtap P, Mizushima N. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat Chem Biol. 2005;1:112–9.
Cho YS, Challa S, Moquin D, Genga R, Ray TD, Guildford M, et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell. 2009;137:1112–23.
Yu L, Guo Q, Li Y, Mao M, Liu Z, Li T, et al. CHMP4C promotes pancreatic cancer progression by inhibiting necroptosis via the RIPK1/RIPK3/MLKL pathway. J Adv Res. 2025;77:653–68.
Li Y, Ye R, Dai H, Lin J, Cheng Y, Zhou Y, et al. Exploring TNFR1: from discovery to targeted therapy development. J Transl Med. 2025;23:71.
Shaw JJP, Guy C, Tummers B, Green DR. FLIP(L) permits apoptotic and inflammatory signaling and inhibits necroptosis in mice without Caspase-8 oligomerization. Proc Natl Acad Sci USA. 2025;122:e2415992122.
Tang J, Zhuang Y, Zhang Y, Hu H, Wang H, Xu H, et al. Necroptosis in cancer: insight from epigenetic, post-transcriptional and post-translational modifications. J Hematol Oncol. 2025;18:77.
Xu L, Zhuang C. Mixed Lineage Kinase Domain-Like Protein (MLKL): from mechanisms to therapeutic opportunities. Adv Sci. 2025;12:e09277.
Huang Y, Wang L, Zhu Y, Li X, Dai Y, He G, et al. Z-DNA-binding protein 1-mediated programmed cell death: mechanisms and therapeutic implications. Chin Med J. 2025;138:2421–51.
Ye K, Chen Z, Xu Y. The double-edged functions of necroptosis. Cell Death Dis. 2023;14:163.
Krysko O, Aaes TL, Kagan VE, D’Herde K, Bachert C, Leybaert L, et al. Necroptotic cell death in anti-cancer therapy. Immunol Rev. 2017;280:207–19.
Weinlich R, Oberst A, Beere HM, Green DR. Necroptosis in development, inflammation and disease. Nat Rev Mol Cell Biol. 2017;18:127–36.
Yan J, Wan P, Choksi S, Liu ZG. Necroptosis and tumor progression. Trends Cancer. 2022;8:21–27.
Nam YW, Shin JH, Kim S, Hwang CH, Lee CS, Hwang G, et al. EGFR inhibits TNF-α-mediated pathway by phosphorylating TNFR1 at tyrosine 360 and 401. Cell Death Differ. 2024;31:1318–32.
van Loo G, Bertrand MJM. Death by TNF: a road to inflammation. Nat Rev Immunol. 2023;23:289–303.
Meier P, Legrand AJ, Adam D, Silke J. Immunogenic cell death in cancer: targeting necroptosis to induce antitumour immunity. Nat Rev Cancer. 2024;24:299–315.
Ju E, Park KA, Shen HM, Hur GM. The resurrection of RIP kinase 1 as an early cell death checkpoint regulator-a potential target for therapy in the necroptosis era. Exp Mol Med. 2022;54:1401–11.
Ermolaeva MA, Michallet MC, Papadopoulou N, Utermöhlen O, Kranidioti K, Kollias G, et al. Function of TRADD in tumor necrosis factor receptor 1 signaling and in TRIF-dependent inflammatory responses. Nat Immunol. 2008;9:1037–46.
Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81:495–504.
Wang L, Chang X, Feng J, Yu J, Chen G. TRADD mediates RIPK1-independent necroptosis induced by tumor necrosis factor. Front Cell Dev Biol. 2019;7:393.
McComb S, Cheung H, Korneluk R, Wang S, Krishnan L, Sad SJCD, et al. cIAP1 and cIAP2 limit macrophage necroptosis by inhibiting Rip1 and Rip3 activation. Cell Death Differ. 2012;19:1791–801.
Wagner J, Vredevoogd D, Yu X, Lu D, Peeper DS, Hermanns HM, et al. TRAF2 and RIPK1 redundantly mediate classical NFκB signaling by TNFR1 and CD95-type death receptors. Cell Death Dis. 2025;16:35.
Piao X, Byun HS, Lee SR, Ju E, Park KA, Sohn KC, et al. 8-Geranylumbelliferone isolated from Paramignya trimera triggers RIPK1/RIPK3-dependent programmed cell death upon TNFR1 ligation. Biochem Pharmacol. 2021;192:114733.
Zhang B, Orning P, Lehman JW, Dinis A, Torres-Ulloa L, Elling R, et al. Raver1 links Ripk1 RNA splicing to caspase-8-mediated pyroptotic cell death, inflammation, and pathogen resistance. Proc Natl Acad Sci USA. 2025;122:e2420802122.
Ha J, Kim M, Seo D, Park JS, Lee J, Lee J, et al. The deubiquitinating enzyme USP20 regulates the TNFα-induced NF-κB signaling pathway through stabilization of p62. Int J Mol Sci. 2020;21:3116.
Draber P, Kupka S, Reichert M, Draberova H, Lafont E, de Miguel D, et al. LUBAC-recruited CYLD and A20 regulate gene activation and cell death by exerting opposing effects on linear ubiquitin in signaling complexes. Cell Rep. 2015;13:2258–72.
Mannion J, Gifford V, Bellenie B, Fernando W, Ramos Garcia L, Wilson R, et al. A RIPK1-specific PROTAC degrader achieves potent antitumor activity by enhancing immunogenic cell death. Immunity. 2024;57:1514–32.e15.
Yang CY, Tseng YC, Tu YF, Kuo BJ, Hsu LC, Lien CI, et al. Reverse hierarchical DED assembly in the cFLIP-procaspase-8 and cFLIP-procaspase-8-FADD complexes. Nat Commun. 2024;15:8974.
Yang ZH, Wu XN, He P, Wang X, Wu J, Ai T, et al. A non-canonical PDK1-RSK signal diminishes pro-caspase-8-mediated necroptosis blockade. Mol Cell. 2020;80:296–310.e296.
Martinez Lagunas K, Savcigil DP, Zrilic M, Carvajal Fraile C, Craxton A, Self E, et al. Cleavage of cFLIP restrains cell death during viral infection and tissue injury and favors tissue repair. Sci Adv. 2023;9:eadg2829.
Davidovich P, Higgins CA, Najda Z, Longley DB, Martin SJ. cFLIP(L) acts as a suppressor of TRAIL- and Fas-initiated inflammation by inhibiting assembly of caspase-8/FADD/RIPK1 NF-κB-activating complexes. Cell Rep. 2023;42:113476.
Chen D, Zhao Z, Hong R, Yang D, Gong Y, Wu Q, et al. Harnessing the FGFR2/NF2/YAP signaling-dependent necroptosis to develop an FGFR2/IL-8 dual blockade therapeutic strategy. Nat Commun. 2025;16:4128.
Cai Z, Jitkaew S, Zhao J, Chiang HC, Choksi S, Liu J, et al. Plasma membrane translocation of trimerized MLKL protein is required for TNF-induced necroptosis. Nat Cell Biol. 2014;16:55–65.
Chen X, Li W, Ren J, Huang D, He WT, Song Y, et al. Translocation of mixed lineage kinase domain-like protein to plasma membrane leads to necrotic cell death. Cell Res. 2014;24:105–121.
Baik JY, Liu Z, Jiao D, Kwon HJ, Yan J, Kadigamuwa C, et al. ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer. Nat Commun. 2021;12:2666.
Chen XY, Dai YH, Wan XX, Hu XM, Zhao WJ, Ban XX, et al. ZBP1-mediated necroptosis: mechanisms and therapeutic implications. Molecules. 2022;28:52.
Newton K, Wickliffe KE, Maltzman A, Dugger DL, Strasser A, Pham VC, et al. RIPK1 inhibits ZBP1-driven necroptosis during development. Nature. 2016;540:129–33.
Lin J, Kumari S, Kim C, Van TM, Wachsmuth L, Polykratis A, et al. RIPK1 counteracts ZBP1-mediated necroptosis to inhibit inflammation. Nature. 2016;540:124–8.
Yang D, Liang Y, Zhao S, Ding Y, Zhuang Q, Shi Q, et al. ZBP1 mediates interferon-induced necroptosis. Cell Mol Immunol. 2020;17:356–68.
Ingram JP, Thapa RJ, Fisher A, Tummers B, Zhang T, Yin C, et al. ZBP1/DAI drives RIPK3-mediated cell death induced by IFNs in the absence of RIPK1. J Immunol. 2019;203:1348–55.
Liao CY, Li G, Kang FP, Lin CF, Xie CK, Wu YD, et al. Necroptosis enhances ‘don’t eat me’ signal and induces macrophage extracellular traps to promote pancreatic cancer liver metastasis. Nat Commun. 2024;15:6043.
Hänggi K, Li J, Gangadharan A, Liu X, Celias DP, Osunmakinde O, et al. Interleukin-1α release during necrotic-like cell death generates myeloid-driven immunosuppression that restricts anti-tumor immunity. Cancer Cell. 2024;42:2015–31.e2011.
Gou Q, Yan B, Duan Y, Guo Y, Qian J, Shi J, et al. Ubiquitination of CD47 regulates innate anti-tumor immune response. Adv Sci. 2025;12:e2412205.
Liang W, Liu H, Zeng Z, Liang Z, Xie H, Li W, et al. KRT17 promotes T-lymphocyte infiltration through the YTHDF2-CXCL10 axis in colorectal cancer. Cancer Immunol Res. 2023;11:875–94.
Liang JH, Tian XG, Zhou MR, Yan F, Fan JL, Qin Y, et al. Shikonin and chitosan-silver nanoparticles synergize against triple-negative breast cancer through RIPK3-triggered necroptotic immunogenic cell death. Biomaterials. 2024;309:122608.
Zhang Z, Zhang F, Xie W, Niu Y, Wang H, Li G, et al. Induced necroptosis and its role in cancer immunotherapy. Int J Mol Sci. 2024;25:10760.
Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.
Tan Y, Sementino E, Cheung M, Peri S, Menges CW, Kukuyan AM, et al. Somatic epigenetic silencing of RIPK3 inactivates necroptosis and contributes to chemoresistance in malignant mesothelioma. Clin Cancer Res. 2021;27:1200–13.
Koo GB, Morgan MJ, Lee DG, Kim WJ, Yoon JH, Koo JS, et al. Methylation-dependent loss of RIP3 expression in cancer represses programmed necrosis in response to chemotherapeutics. Cell Res. 2015;25:707–25.
Bozec D, Iuga AC, Roda G, Dahan S, Yeretssian G. Critical function of the necroptosis adaptor RIPK3 in protecting from intestinal tumorigenesis. Oncotarget. 2016;7:46384–400.
Feng X, Song Q, Yu A, Tang H, Peng Z, Wang X. Receptor-interacting protein kinase 3 is a predictor of survival and plays a tumor suppressive role in colorectal cancer. Neoplasma. 2015;62:592–601.
Nugues AL, El Bouazzati H, Hétuin D, Berthon C, Loyens A, Bertrand E, et al. RIP3 is downregulated in human myeloid leukemia cells and modulates apoptosis and caspase-mediated p65/RelA cleavage. Cell Death Dis. 2014;5:e1384.
Geserick P, Wang J, Schilling R, Horn S, Harris PA, Bertin J, et al. Absence of RIPK3 predicts necroptosis resistance in malignant melanoma. Cell Death Dis. 2015;6:e1884.
McCabe KE, Bacos K, Lu D, Delaney JR, Axelrod J, Potter MD, et al. Triggering necroptosis in cisplatin and IAP antagonist-resistant ovarian carcinoma. Cell Death Dis. 2014;5:e1496.
Ertao Z, Jianhui C, Kang W, Zhijun Y, Hui W, Chuangqi C, et al. Prognostic value of mixed lineage kinase domain-like protein expression in the survival of patients with gastric caner. Tumour Biol. 2016;37:13679–85.
Colbert LE, Fisher SB, Hardy CW, Hall WA, Saka B, Shelton JW, et al. Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma. Cancer. 2013;119:3148–55.
Li X, Guo J, Ding AP, Qi WW, Zhang PH, Lv J, et al. Association of mixed lineage kinase domain-like protein expression with prognosis in patients with colon cancer. Technol Cancer Res Treat. 2017;16:428–34.
Wang Q, Chen W, Xu X, Li B, He W, Padilla MT, et al. RIP1 potentiates BPDE-induced transformation in human bronchial epithelial cells through catalase-mediated suppression of excessive reactive oxygen species. Carcinogenesis. 2013;34:2119–28.
Park S, Hatanpaa KJ, Xie Y, Mickey BE, Madden CJ, Raisanen JM, et al. The receptor interacting protein 1 inhibits p53 induction through NF-kappaB activation and confers a worse prognosis in glioblastoma. Cancer Res. 2009;69:2809–16.
Seifert L, Werba G, Tiwari S, Giao Ly NN, Alothman S, Alqunaibit D, et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature. 2016;532:245–9.
Wang S, Guo S, Guo J, Du Q, Wu C, Wu Y, et al. Cell death pathways: molecular mechanisms and therapeutic targets for cancer. MedComm. 2024;5:e693.
Lei K, Chen J, Deng Y, Peng Y, Zhai X, Ren X, et al. Cracking the code of cancer immunotherapy resistance: emerging roles of pyroptosis and necroptosis. J Exp Clin Cancer Res. 2025;44:308.
Mázló A, Jenei V, Burai S, Molnár T, Bácsi A, Koncz G. Types of necroinflammation, the effect of cell death modalities on sterile inflammation. Cell Death Dis. 2022;13:423.
Oliver Metzig M, Fuchs D, Tagscherer KE, Gröne HJ, Schirmacher P, Roth W. Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene. 2016;35:3399–409.
Rucker AJ, Park CS, Li QJ, Moseman EA, Chan FK. Necroptosis stimulates interferon-mediated protective anti-tumor immunity. Cell Death Dis. 2024;15:403.
Moriwaki K, Chan FK. Regulation of RIPK3- and RHIM-dependent necroptosis by the proteasome. J Biol Chem. 2016;291:5948–59.
Deeraksa A, Pan J, Sha Y, Liu XD, Eissa NT, Lin SH, et al. Plk1 is upregulated in androgen-insensitive prostate cancer cells and its inhibition leads to necroptosis. Oncogene. 2013;32:2973–83.
Liu X, Chhipa RR, Nakano I, Dasgupta B. The AMPK inhibitor compound C is a potent AMPK-independent antiglioma agent. Mol Cancer Ther. 2014;13:596–605.
Xiong K, Qian C, Yuan Y, Wei L, Liao X, He L, et al. Necroptosis induced by Ruthenium(II) complexes as dual catalytic inhibitors of topoisomerase I/II. Angew Chem Int Ed Engl. 2020;59:16631–7.
Lu B, Gong X, Wang ZQ, Ding Y, Wang C, Luo TF, et al. Shikonin induces glioma cell necroptosis in vitro by ROS overproduction and promoting RIP1/RIP3 necrosome formation. Acta Pharmacol Sin. 2017;38:1543–53.
Chen X, Yang L, Oppenheim JJ, Howard MZ. Cellular pharmacology studies of shikonin derivatives. Phytother Res. 2002;16:199–209.
Shahsavari Z, Karami-Tehrani F, Salami S, Ghasemzadeh M. RIP1K and RIP3K provoked by shikonin induce cell cycle arrest in the triple negative breast cancer cell line, MDA-MB-468: necroptosis as a desperate programmed suicide pathway. Tumour Biol. 2016;37:4479–91.
Li S, Zhang T, Xu W, Ding J, Yin F, Xu J, et al. Sarcoma-targeting peptide-decorated polypeptide nanogel intracellularly delivers Shikonin for upregulated osteosarcoma necroptosis and diminished pulmonary metastasis. Theranostics. 2018;8:1361–75.
Huang X, Jin J, Qian W, Ye X. Shikonin overcomes drug resistance and induces necroptosis by regulating the Mir-92a-1-5p/Mlkl axis in chronic myeloid leukemia cells. Blood. 2019;134:1633.
Markowitsch SD, Juetter KM, Schupp P, Hauschulte K, Vakhrusheva O, Slade KS, et al. Shikonin reduces growth of docetaxel-resistant prostate cancer cells mainly through necroptosis. Cancers. 2021;13:882.
Dunai ZA, Imre G, Barna G, Korcsmaros T, Petak I, Bauer PI, et al. Staurosporine induces necroptotic cell death under caspase-compromised conditions in U937 cells. PLoS ONE. 2012;7:e41945.
Xu B, Xu M, Tian Y, Yu Q, Zhao Y, Chen X, et al. Matrine induces RIP3-dependent necroptosis in cholangiocarcinoma cells. Cell Death Discov. 2017;3:16096.
Guo D, Zhang W, Yang H, Bi J, Xie Y, Cheng B, et al. Celastrol induces necroptosis and ameliorates inflammation via targeting biglycan in human gastric carcinoma. Int J Mol Sci. 2019;20:5716.
Han Q, Ma Y, Wang H, Dai Y, Chen C, Liu Y, et al. Resibufogenin suppresses colorectal cancer growth and metastasis through RIP3-mediated necroptosis. J Transl Med. 2018;16:201.
Lin CY, Chang TW, Hsieh WH, Hung MC, Lin IH, Lai SC, et al. Simultaneous induction of apoptosis and necroptosis by Tanshinone IIA in human hepatocellular carcinoma HepG2 cells. Cell Death Discov. 2016;2:16065.
Zhou J, Li G, Han G, Feng S, Liu Y, Chen J, et al. Emodin induced necroptosis in the glioma cell line U251 via the TNF-α/RIP1/RIP3 pathway. Investig New Drugs. 2020;38:50–9.
Shao CS, Feng N, Zhou S, Zheng XX, Wang P, Zhang JS, et al. Ganoderic acid T improves the radiosensitivity of HeLa cells via converting apoptosis to necroptosis. Toxicol Res. 2021;10:531–41.
Button RW, Lin F, Ercolano E, Vincent JH, Hu B, Hanemann CO, et al. Artesunate induces necrotic cell death in schwannoma cells. Cell Death Dis. 2014;5:e1466.
Li Y, Gong P, Kong C, Tian X. Bufalin engages in RIP1-dependent and ROS-dependent programmed necroptosis in breast cancer cells by targeting the RIP1/RIP3/PGAM5 pathway. Anti-cancer Drugs. 2019;30:e0770.
Lu Z, Wu C, Zhu M, Song W, Wang H, Wang J, et al. Ophiopogonin D’ induces RIPK1‑dependent necroptosis in androgen‑dependent LNCaP prostate cancer cells. Int J Oncol. 2020;56:439–47.
Feng L, Sang J, Zhu H, Hu Y, Liu B, He G, et al. Tumor microenvironment-activated Fe(3+)-doped dendritic mesoporous organosilica nanocomposites as ferroptosis inducers for enhanced immunotherapy. Adv Mater. 2025;37:e10010.
Zhang S, Li S, Zhao X, Lv W, Zhao Y, Zhong L, et al. Triple-Kill nano-disruptor integrating ion interference, metabolic inhibition, and immune activation for augmented apoptosis and pyroptosis-mediated immunotherapy. Adv Mater. 2025;38:e16688.
Xiong Y, Rao Y, Hu J, Luo Z, Chen C. Nanoparticle-based photothermal therapy for breast cancer noninvasive treatment. Adv Mater. 2025;37:e2305140.
Wang Y, Xu Y, Song J, Liu X, Liu S, Yang N, et al. Tumor cell-targeting and tumor microenvironment-responsive nanoplatforms for the multimodal imaging-guided photodynamic/photothermal/chemodynamic treatment of cervical cancer. Int J Nanomed. 2024;19:5837–58.
Li S, Lui KH, Lau WS, Chen J, Lo WS, Li X, et al. MSOT-guided nanotheranostics for synergistic mild photothermal therapy and chemotherapy to boost necroptosis/apoptosis. ACS Appl Mater Interfaces. 2022;14:33712–33372.
Pang Y, Guo J, Ma Q, Qi J, Liu L, Bu Y, et al. Hyaluronic acid-functionalized bismuth vanadate/molybdenum disulfide nanoheterojunctions achieve efficient phototherapy of hypoxic tumor. Biomater Res. 2025;29:0228.
Cai R, Wang M, Liu M, Zhu X, Feng L, Yu Z, et al. An iRGD-conjugated photothermal therapy-responsive gold nanoparticle system carrying siCDK7 induces necroptosis and immunotherapeutic responses in lung adenocarcinoma. Bioeng Transl Med. 2023;8:e10430.
Nicosia A, Cavallaro G, Costa S, Utzeri MA, Cuttitta A, Giammona G, et al. Carbon nanodots for on demand chemophotothermal therapy combination to elicit necroptosis: overcoming apoptosis resistance in breast cancer cell lines. Cancers. 2020;12:3114.
Xie W, Lu J, Guo Z, Guo X, Chi Y, Ye J, et al. Necroptosis-elicited host immunity: GOx-loaded MoS2 nanocatalysts for self-amplified chemodynamic immunotherapy. Nano Res. 2022;15:2244–53.
Zhao H, Chen H, Guo Z, Zhang W, Yu H, Zhuang Z, et al. In situ photothermal activation of necroptosis potentiates black phosphorus-mediated cancer photo-immunotherapy. Chem Eng J. 2020;394:124314.
Han F, Zhou X, Wang Z, Cai L, Zhang H, Shi T, et al. Red-light triggered h-abstraction photoinitiators for the efficient oxygen-independent therapy of hypoxic tumors. Angew Chem Int Ed Engl. 2024;136:e202408769.
de Melo Gomes LC, de Oliveira Cunha AB, Peixoto LFF, Zanon RG, Botelho FV, Silva MJB, et al. Photodynamic therapy reduces cell viability, migration and triggers necroptosis in prostate tumor cells. Photochem Photobiol Sci. 2023;22:1341–56.
de Almeida DRQ, Dos Santos AF, Wailemann RAM, Terra LF, Gomes VM, Arini GS, et al. Necroptosis activation is associated with greater methylene blue-photodynamic therapy-induced cytotoxicity in human pancreatic ductal adenocarcinoma cells. Photochem Photobiol Sci. 2023;22:729–44.
Dos Santos AF, Inague A, Arini GS, Terra LF, Wailemann RAM, Pimentel AC, et al. Distinct photo-oxidation-induced cell death pathways lead to selective killing of human breast cancer cells. Cell Death Dis. 2020;11:1070.
Wang L, Chelakkot VS, Newhook N, Tucker S, Hirasawa K. Inflammatory cell death induced by 5-aminolevulinic acid-photodynamic therapy initiates anticancer immunity. Front Oncol. 2023;13:1156763.
Mohammadalipour Z, Rahmati M, Khataee A, Moosavi MA. Differential effects of N-TiO(2) nanoparticle and its photo-activated form on autophagy and necroptosis in human melanoma A375 cells. J Cell Physiol. 2020;235:8246–59.
Gao WJ, Wang MM, Su Y, Yu ZH, Liu HK, Su Z. Self-assembly mitochondria-targeting donor-acceptor type theranostic nanosphere activates ROS storm for multimodal cancer therapy. ACS Appl Bio Mater. 2023;6:722–32.
Zheng Q, Zou T, Wang W, Zhang C, Hu S, Cheng X, et al. Necroptosis-mediated synergistic photodynamic and glutamine-metabolic therapy enabled by a biomimetic targeting nanosystem for cholangiocarcinoma. Adv Sci. 2024;11:e2309203.
Han B, Liu Y, Zhou Q, Yu Y, Liu X, Guo Y, et al. The advance of ultrasound-enabled diagnostics and therapeutics. J Control Release. 2024;375:1–19.
Zang P, Yu C, Zhang R, Yang D, Gai S, Yang P, et al. Revealing the optimization route of piezoelectric sonosensitizers: from mechanism to engineering methods. Small. 2024;20:e2401650.
Ouyang J, Tang Z, Farokhzad N, Kong N, Kim NY, Feng C, et al. Ultrasound mediated therapy: recent progress and challenges in nanoscience. Nano Today. 2020;35:100949.
Um W, Ko H, You DG, Lim S, Kwak G, Shim MK, et al. Necroptosis-inducible polymeric nanobubbles for enhanced cancer sonoimmunotherapy. Adv Mater. 2020;32:e1907953.
Xu X, Shabiti S, Zhang X, Zheng J, Liang N, Wang Z, et al. Membrane-anchoring clickable Iridium (III) nanosonosensitizer in situ evokes PANoptosis for augmented tumor sono-immunotherapy. Nano Today. 2024;56:102270.
Tian H, Shang H, Chen Y, Wu B, Wang C, Wang X, et al. Sonosensitizer nanoplatforms augmented sonodynamic therapy-sensitizing shikonin-induced necroptosis against hepatocellular carcinoma. Int J Nanomed. 2023;18:7079–92.
Du Y, Yang J, He F, Zhao X, Zhou J, Zang P, et al. Revealing the mutually enhanced mechanism of necroptosis and immunotherapy induced by defect engineering and piezoelectric effect. Adv Mater. 2024;36:e2304322.
Chu T, Maksoudian C, Pedrotti S, Izci M, Perez Gilabert I, Koutsoumpou X, et al. Nanomaterial-mediated delivery of MLKL plasmids sensitizes tumors to immunotherapy and reduces metastases. Adv Healthc Mater. 2024;13:2401306.
Kim S, Kim S, Kim S, Lee NE, Lee SH, Kim H, et al. Improvement of therapeutic effect via inducing non-apoptotic cell death using mRNA-protection nanocage. Adv Healthc Mater. 2024;13:2400240.
Yu S, Li J, Zhang J, Zeng G, Zeng B, Song S, et al. Nanosized shikonin disrupts tumor-cell mismatch repair and synergizes with manganese to sensitize squamous carcinoma to immunotherapy. ACS Nano. 2025;19:13889–905.
Shi W, Feng W, Li S, Cui Y, Liu S, Jiang H, et al. Ferroptosis and necroptosis produced autologous tumor cell lysates co-delivering with combined immnoadjuvants as personalized in situ nanovaccines for antitumor immunity. ACS Nano. 2023;17:14475–93.
Feng W, Shi W, Liu S, Liu H, Liu Y, Ge P, et al. Fe(III)-Shikonin supramolecular nanomedicine for combined therapy of tumor via ferroptosis and necroptosis. Adv Healthc Mater. 2022;11:e2101926.
Li X, Duan Z, Chen X, Pan D, Luo Q, Gu L, et al. Impairing tumor metabolic plasticity via a stable metal-phenolic-based polymeric nanomedicine to suppress colorectal cancer. Adv Mater. 2023;35:e2300548.
Lee S, Ko MJ, Avritscher R, Lewandowski RJ, Kim DH. Cryo-Nanocatalyst enhances therapeutic efficacy of cryo-immunotherapy through necroptosis and local delivery of programmed death-ligand 1 inhibitors. ACS Nano. 2024;18:24269–82.
Wang H, Sun L, Su L, Rizo J, Liu L, Wang LF, et al. Mixed lineage kinase domain-like protein MLKL causes necrotic membrane disruption upon phosphorylation by RIP3. Mol Cell. 2014;54:133–46.
Wu Q, He X, Wu LM, Zhang RY, Li LM, Wu CM, et al. MLKL aggravates Ox-LDL-induced cell pyroptosis via activation of NLRP3 inflammasome in human umbilical vein endothelial cells. Inflammation. 2020;43:2222–31.
Philipp S, Sosna J, Adam D. Cancer and necroptosis: friend or foe? Cell Mol Life Sci. 2016;73:2183–93.
Micheau O, Tschopp J. Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes. Cell. 2003;114:181–90.
Dhuriya YK, Sharma D. Necroptosis: a regulated inflammatory mode of cell death. J Neuroinflammation. 2018;15:199.
Li J, Cui S, Li Y, Bai J, Zhang C, Li K, et al. TNF-α mediates activation of neuronal necroptotic signaling in rat with syringomyelia. Exp Neurol. 2025;388:115214.
Saeki Y, Okita Y, Igashira-Oguro E, Udagawa C, Murata A, Tanaka T, et al. Modulation of TNFR 1-triggered two opposing signals for inflammation and apoptosis via RIPK 1 disruption by geldanamycin in rheumatoid arthritis. Clin Rheumatol. 2021;40:2395–405.
Bai L, Smith DC, Wang S. Small-molecule SMAC mimetics as new cancer therapeutics. Pharmacol Ther. 2014;144:82–95.
Dondelinger Y, Aguileta MA, Goossens V, Dubuisson C, Grootjans S, Dejardin E, et al. RIPK3 contributes to TNFR1-mediated RIPK1 kinase-dependent apoptosis in conditions of cIAP1/2 depletion or TAK1 kinase inhibition. Cell Death Differ. 2013;20:1381–92.
Moquin DM, McQuade T, Chan FK. CYLD deubiquitinates RIP1 in the TNFα-induced necrosome to facilitate kinase activation and programmed necrosis. PLoS ONE. 2013;8:e76841.
Wright A, Reiley WW, Chang M, Jin W, Lee AJ, Zhang M, et al. Regulation of early wave of germ cell apoptosis and spermatogenesis by deubiquitinating enzyme CYLD. Dev Cell. 2007;13:705–16.
O’Donnell MA, Perez-Jimenez E, Oberst A, Ng A, Massoumi R, Xavier R, et al. Caspase 8 inhibits programmed necrosis by processing CYLD. Nat Cell Biol. 2011;13:1437–42.
Li X, Li F, Zhang X, Zhang H, Zhao Q, Li M, et al. Caspase-8 auto-cleavage regulates programmed cell death and collaborates with RIPK3/MLKL to prevent lymphopenia. Cell Death Differ. 2022;29:1500–12.
Garcia-Calvo M, Peterson EP, Leiting B, Ruel R, Nicholson DW, Thornberry NA. Inhibition of human caspases by peptide-based and macromolecular inhibitors. J Biol Chem. 1998;273:32608–13.
Li J, McQuade T, Siemer AB, Napetschnig J, Moriwaki K, Hsiao YS, et al. The RIP1/RIP3 necrosome forms a functional amyloid signaling complex required for programmed necrosis. Cell. 2012;150:339–50.
Morgan MJ, Kim YS. Roles of RIPK3 in necroptosis, cell signaling, and disease. Exp Mol Med. 2022;54:1695–704.
Mandal P, Berger SB, Pillay S, Moriwaki K, Huang C, Guo H, et al. RIP3 induces apoptosis independent of pronecrotic kinase activity. Mol Cell. 2014;56:481–95.
Sun L, Wang H, Wang Z, He S, Chen S, Liao D, et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell. 2012;148:213–27.
Zhao J, Jitkaew S, Cai Z, Choksi S, Li Q, Luo J, et al. Mixed lineage kinase domain-like is a key receptor interacting protein 3 downstream component of TNF-induced necrosis. Proc Natl Acad Sci USA. 2012;109:5322–7.
Yan B, Liu L, Huang S, Ren Y, Wang H, Yao Z, et al. Discovery of a new class of highly potent necroptosis inhibitors targeting the mixed lineage kinase domain-like protein. Chem Commun. 2017;53:3637–40.
Wang X, Ros U, Agrawal D, Keller EC, Slotta-Huspenina J, Dill V, et al. MLKL promotes cellular differentiation in myeloid leukemia by facilitating the release of G-CSF. Cell Death Differ. 2021;28:3235–50.
He L, Peng K, Liu Y, Xiong J, Zhu FF. Low expression of mixed lineage kinase domain-like protein is associated with poor prognosis in ovarian cancer patients. Onco Targets Ther. 2013;6:1539–43.

