Pancreatic cancer is a devastating gastrointestinal cancer characterized by late diagnosis, limited treatment success and dismal prognosis. Exocrine tumours account for 95% of pancreatic cancers and the most common pathological type is pancreatic ductal adenocarcinoma (PDAC). The occurrence and progression of PDAC involve multiple factors, including internal genetic alterations and external inflammatory stimuli. The biology and therapeutic response of PDAC are further shaped by various forms of regulated cell death, such as apoptosis, necroptosis, ferroptosis, pyroptosis and alkaliptosis. Cell death induced by local or systemic treatments suppresses tumour proliferation, invasion and metastasis. However, unrestricted cell death or tissue damage might result in an inflammation-related immunosuppressive microenvironment, which is conducive to tumour progression or recurrence. The precise extent to which cell death affects PDAC is not yet well described. A growing body of preclinical and clinical studies document significant correlations between mutations (for example, in KRAS and TP53), stress responses (such as hypoxia and autophagy), metabolic reprogramming and chemotherapeutic responses. Here, we describe the molecular machinery of cell death, discuss the complexity and multifaceted nature of lethal signalling in PDAC cells, and highlight the challenges and opportunities for activating cell death pathways through precision oncology treatments.
The morbidity and mortality of pancreatic cancer continue to increase and constitute a major challenge for basic and applied oncology.
Regulated cell death occurs through apoptotic and non-apoptotic pathways, manifesting in different morphological, biochemical and genetic characteristics.
Regulated cell death plays a dual role in pancreatic cancer and has been shown to have both pro-tumorigenic and tumour-suppressive effects.
Endogenous damage-associated molecular patterns released from stressed, dying or dead cells play a key role in regulating inflammation and immune responses in the pancreatic tumour microenvironment.
A concerted preclinical and clinical evaluation is needed to determine whether therapies can induce adequate cell death responses.
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Siegel, R. L., Miller, K. D. & Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin. 70, 7–30 (2020).
Kleeff, J. et al. Pancreatic cancer. Nat. Rev. Dis. Prim. 2, 16022 (2016).
Rawla, P., Sunkara, T. & Gaduputi, V. Epidemiology of pancreatic cancer: global trends, etiology and risk factors. World J. Oncol. 10, 10–27 (2019).
Sarantis, P., Koustas, E., Papadimitropoulou, A., Papavassiliou, A. G. & Karamouzis, M. V. Pancreatic ductal adenocarcinoma: treatment hurdles, tumor microenvironment and immunotherapy. World J. Gastrointest. Oncol. 12, 173–181 (2020).
Tesfaye, A. A. & Philip, P. A. Adjuvant treatment of surgically resectable pancreatic ductal adenocarcinoma. Clin. Adv. Hematol. Oncol. 17, 54–63 (2019).
Neoptolemos, J. P. et al. Therapeutic developments in pancreatic cancer: current and future perspectives. Nat. Rev. Gastroenterol. Hepatol. 15, 333–348 (2018).
Nevala-Plagemann, C., Hidalgo, M. & Garrido-Laguna, I. From state-of-the-art treatments to novel therapies for advanced-stage pancreatic cancer. Nat. Rev. Clin. Oncol. 17, 108–123 (2020).
Ho, W. J., Jaffee, E. M. & Zheng, L. The tumour microenvironment in pancreatic cancer - clinical challenges and opportunities. Nat. Rev. Clin. Oncol. 17, 527–540 (2020).
Hosein, A. N., Brekken, R. A. & Maitra, A. Pancreatic cancer stroma: an update on therapeutic targeting strategies. Nat. Rev. Gastroenterol. Hepatol. 17, 487–505 (2020).
Quinonero, F. et al. The challenge of drug resistance in pancreatic ductal adenocarcinoma: a current overview. Cancer Biol. Med. 16, 688–699 (2019).
Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).
Tang, D., Kang, R., Berghe, T. V., Vandenabeele, P. & Kroemer, G. The molecular machinery of regulated cell death. Cell Res. 29, 347–364 (2019).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Lee, S. Y. et al. Regulation of tumor progression by programmed necrosis. Oxid. Med. Cell. Longev. 2018, 3537471 (2018).
Chen, X., Kang, R., Kroemer, G. & Tang, D. Broadening horizons: the role of ferroptosis in cancer. Nat. Rev. Clin. Oncol. 18, 280–296 (2021).
Kerr, J. F., Wyllie, A. H., & Currie, A. R. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br. J. Cancer 26, 239–257 (1972).
Miller-Ocuin, J. L. et al. DNA released from neutrophil extracellular traps (NETs) activates pancreatic stellate cells and enhances pancreatic tumor growth. Oncoimmunology 8, e1605822 (2019).
Miyatake, Y. et al. Visualising the dynamics of live pancreatic microtumours self-organised through cell-in-cell invasion. Sci. Rep. 8, 14054 (2018).
Carneiro, B. A. & El-Deiry, W. S. Targeting apoptosis in cancer therapy. Nat. Rev. Clin. Oncol. 17, 395–417 (2020).
Li, P. et al. Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell 91, 479–489 (1997).
Du, C., Fang, M., Li, Y., Li, L. & Wang, X. Smac, a mitochondrial protein that promotes cytochrome c-dependent caspase activation by eliminating IAP inhibition. Cell 102, 33–42 (2000).
Susin, S. A. et al. Molecular characterization of mitochondrial apoptosis-inducing factor. Nature 397, 441–446 (1999).
Li, L. Y., Luo, X. & Wang, X. Endonuclease G is an apoptotic DNase when released from mitochondria. Nature 412, 95–99 (2001).
Singh, R., Letai, A. & Sarosiek, K. Regulation of apoptosis in health and disease: the balancing act of BCL-2 family proteins. Nat. Rev. Mol. Cell Biol. 20, 175–193 (2019).
Shimizu, S., Narita, M. & Tsujimoto, Y. Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature 399, 483–487 (1999).
Marzo, I. et al. Bax and adenine nucleotide translocator cooperate in the mitochondrial control of apoptosis. Science 281, 2027–2031 (1998).
Luo, X., Budihardjo, I., Zou, H., Slaughter, C. & Wang, X. Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell 94, 481–490 (1998).
Montero, J. & Letai, A. Why do BCL-2 inhibitors work and where should we use them in the clinic? Cell Death Differ. 25, 56–64 (2018).
Campani, D. et al. Bcl-2 expression in pancreas development and pancreatic cancer progression. J. Pathol. 194, 444–450 (2001).
Song, S., Wang, B., Gu, S., Li, X. & Sun, S. Expression of Beclin 1 and Bcl-2 in pancreatic neoplasms and its effect on pancreatic ductal adenocarcinoma prognosis. Oncol. Lett. 14, 7849–7861 (2017).
Miyamoto, Y. et al. Immunohistochemical analysis of Bcl-2, Bax, Bcl-X, and Mcl-1 expression in pancreatic cancers. Oncology 56, 73–82 (1999).
Holler, N. et al. Fas triggers an alternative, caspase-8-independent cell death pathway using the kinase RIP as effector molecule. Nat. Immunol. 1, 489–495 (2000).
Degterev, A. et al. Chemical inhibitor of nonapoptotic cell death with therapeutic potential for ischemic brain injury. Nat. Chem. Biol. 1, 112–119 (2005).
Weinlich, R., Oberst, A., Beere, H. M. & Green, D. R. Necroptosis in development, inflammation and disease. Nat. Rev. Mol. Cell Biol. 18, 127–136 (2017).
Galluzzi, L., Kepp, O., Chan, F. K. & Kroemer, G. Necroptosis: mechanisms and relevance to disease. Annu. Rev. Pathol. 12, 103–130 (2017).
Zhang, D. W. et al. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science 325, 332–336 (2009).
He, S. et al. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell 137, 1100–1111 (2009).
Cho, Y. S. et al. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virus-induced inflammation. Cell 137, 1112–1123 (2009).
Sun, L. et al. Mixed lineage kinase domain-like protein mediates necrosis signaling downstream of RIP3 kinase. Cell 148, 213–227 (2012).
Temkin, V., Huang, Q., Liu, H., Osada, H. & Pope, R. M. Inhibition of ADP/ATP exchange in receptor-interacting protein-mediated necrosis. Mol. Cell Biol. 26, 2215–2225 (2006).
Los, M. et al. Activation and caspase-mediated inhibition of PARP: a molecular switch between fibroblast necrosis and apoptosis in death receptor signaling. Mol. Biol. Cell 13, 978–988 (2002).
Gomes-Filho, S. M. et al. Aurora A kinase and its activator TPX2 are potential therapeutic targets in KRAS-induced pancreatic cancer. Cell Oncol. 43, 445–460 (2020).
Xie, Y. et al. Inhibition of aurora kinase A induces necroptosis in pancreatic carcinoma. Gastroenterology 153, 1429–1443.e5 (2017).
Wang, J. et al. Phosphorylation-dependent regulation of ALDH1A1 by Aurora kinase A: insights on their synergistic relationship in pancreatic cancer. BMC Biol. 15, 10 (2017).
Kim, E. et al. Phase I study of the combination of alisertib (MLN8237) and gemcitabine in advanced solid tumors. J. Clin. Oncol. 33, 2526–2526 (2020).
Cookson, B. T. & Brennan, M. A. Pro-inflammatory programmed cell death. Trends Microbiol. 9, 113–114 (2001).
Wang, Y. et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature 547, 99–103 (2017).
Cui, J. et al. MST1 suppresses pancreatic cancer progression via ROS-induced pyroptosis. Mol. Cancer Res. 17, 1316–1325 (2019).
Kayagaki, N. et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature 526, 666–671 (2015).
Rogers, C. et al. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 8, 14128 (2017).
Orning, P. et al. Pathogen blockade of TAK1 triggers caspase-8-dependent cleavage of gasdermin D and cell death. Science 362, 1064–1069 (2018).
Taabazuing, C. Y., Okondo, M. C. & Bachovchin, D. A. Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chem. Biol. 24, 507–514.e4 (2017).
Ding, J. et al. Pore-forming activity and structural autoinhibition of the gasdermin family. Nature 535, 111–116 (2016).
Liu, X. et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature 535, 153–158 (2016).
Sborgi, L. et al. GSDMD membrane pore formation constitutes the mechanism of pyroptotic cell death. EMBO J. 35, 1766–1778 (2016).
Kang, R. et al. Lipid peroxidation drives gasdermin d-mediated pyroptosis in lethal polymicrobial sepsis. Cell Host Microbe 24, 97–108.e4 (2018).
Riegman, M. et al. Ferroptosis occurs through an osmotic mechanism and propagates independently of cell rupture. Nat. Cell Biol. 22, 1042–1048 (2020).
Dixon, S. J. et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell 149, 1060–1072 (2012).
Xie, Y. et al. The tumor suppressor p53 limits ferroptosis by blocking DPP4 activity. Cell Rep. 20, 1692–1704 (2017).
Eling, N., Reuter, L., Hazin, J., Hamacher-Brady, A. & Brady, N. R. Identification of artesunate as a specific activator of ferroptosis in pancreatic cancer cells. Oncoscience 2, 517–532 (2015).
Zhu, S. et al. HSPA5 regulates ferroptotic cell death in cancer cells. Cancer Res. 77, 2064–2077 (2017).
Tang, D. & Kroemer, G. Ferroptosis. Curr. Biol. 30, R1292–R1297 (2020).
Yang, W. S. et al. Regulation of ferroptotic cancer cell death by GPX4. Cell 156, 317–331 (2014).
Zou, Y. et al. Plasticity of ether lipids promotes ferroptosis susceptibility and evasion. Nature 585, 603–608 (2020).
Yuan, H., Li, X., Zhang, X., Kang, R. & Tang, D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem. Biophys. Res. Commun. 478, 1338–1343 (2016).
Doll, S. et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat. Chem. Biol. 13, 91–98 (2017).
Kagan, V. E. et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat. Chem. Biol. 13, 81–90 (2017).
Dixon, S. J. et al. Human haploid cell genetics reveals roles for lipid metabolism genes in nonapoptotic cell death. ACS Chem. Biol. 10, 1604–1609 (2015).
Chen, X., Li, J., Kang, R., Klionsky, D. J. & Tang, D. Ferroptosis: machinery and regulation. Autophagy https://doi.org/10.1080/15548627.2020.1810918 (2020).
Hou, W. et al. Autophagy promotes ferroptosis by degradation of ferritin. Autophagy 12, 1425–1428 (2016).
Li, J. et al. Tumor heterogeneity in autophagy-dependent ferroptosis. Autophagy https://doi.org/10.1080/15548627.2021.1872241 (2021).
Doll, S. et al. FSP1 is a glutathione-independent ferroptosis suppressor. Nature 575, 693–698 (2019).
Bersuker, K. et al. The CoQ oxidoreductase FSP1 acts parallel to GPX4 to inhibit ferroptosis. Nature 575, 688–692 (2019).
Kraft, V. A. N. et al. GTP cyclohydrolase 1/tetrahydrobiopterin counteract ferroptosis through lipid remodeling. ACS Cent. Sci. 6, 41–53 (2020).
Dai, E., Meng, L., Kang, R., Wang, X. & Tang, D. ESCRT-III-dependent membrane repair blocks ferroptosis. Biochem. Biophys. Res. Commun. 522, 415–421 (2020).
Zhang, Y. et al. Imidazole ketone erastin induces ferroptosis and slows tumor growth in a mouse lymphoma model. Cell Chem. Biol. 26, 623–633.e9 (2019).
Sun, X. et al. Metallothionein-1G facilitates sorafenib resistance through inhibition of ferroptosis. Hepatology 64, 488–500 (2016).
Chen, X., Kang, R., Kroemer, G., & Tang, D. Targeting ferroptosis in pancreatic cancer: a double-edged sword. Trends Cancer https://doi.org/10.1016/j.trecan.2021.04.005 (2021).
Song, X. et al. JTC801 induces pH-dependent death specifically in cancer cells and slows growth of tumors in mice. Gastroenterology 154, 1480–1493 (2018).
Furlong, I. J., Ascaso, R., Lopez Rivas, A. & Collins, M. K. Intracellular acidification induces apoptosis by stimulating ICE-like protease activity. J. Cell Sci. 110, 653–661 (1997).
Wang, Y. Z. et al. Tissue acidosis induces neuronal necroptosis via ASIC1a channel independent of its ionic conduction. eLife 4, e05682 (2015).
Nakamura, N., Matsuura, A., Wada, Y. & Ohsumi, Y. Acidification of vacuoles is required for autophagic degradation in the yeast, Saccharomyces cerevisiae. J. Biochem. 121, 338–344 (1997).
Galenkamp, K. M. O. et al. Golgi acidification by NHE7 regulates cytosolic pH homeostasis in pancreatic cancer cells. Cancer Discov. 10, 822–835 (2020).
Zhu, S., Liu, J., Kang, R., Yang, M., & Tang, D. Targeting NF-κB-dependent alkaliptosis for the treatment of venetoclax-resistant acute myeloid leukemia cells. Biochem. Biophys. Res. Commun. 562, 55–61 (2021).
Zheng, C. J., Yang, L. L., Liu, J. & Zhong, L. JTC-801 exerts anti-proliferative effects in human osteosarcoma cells by inducing apoptosis. J. Recept. Signal. Transduct. Res. 38, 133–140 (2018).
Buscail, L., Bournet, B. & Cordelier, P. Role of oncogenic KRAS in the diagnosis, prognosis and treatment of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 17, 153–168 (2020).
Weissmueller, S. et al. Mutant p53 drives pancreatic cancer metastasis through cell-autonomous PDGF receptor beta signaling. Cell 157, 382–394 (2014).
Escobar-Hoyos, L. F. et al. Altered RNA splicing by mutant p53 activates oncogenic RAS signaling in pancreatic cancer. Cancer Cell 38, 198–211.e8 (2020).
Collisson, E. A., Bailey, P., Chang, D. K. & Biankin, A. V. Molecular subtypes of pancreatic cancer. Nat. Rev. Gastroenterol. Hepatol. 16, 207–220 (2019).
Kern, S. E. et al. Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827–830 (1992).
Miyashita, T. & Reed, J. C. Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80, 293–299 (1995).
Nakano, K. & Vousden, K. H. PUMA, a novel proapoptotic gene, is induced by p53. Mol. Cell 7, 683–694 (2001).
Oda, E. et al. Noxa, a BH3-only member of the Bcl-2 family and candidate mediator of p53-induced apoptosis. Science 288, 1053–1058 (2000).
Mihara, M. et al. p53 has a direct apoptogenic role at the mitochondria. Mol. Cell 11, 577–590 (2003).
Fiorini, C. et al. Mutant p53 stimulates chemoresistance of pancreatic adenocarcinoma cells to gemcitabine. Biochim. Biophys. Acta 1853, 89–100 (2015).
Izetti, P. et al. PRIMA-1, a mutant p53 reactivator, induces apoptosis and enhances chemotherapeutic cytotoxicity in pancreatic cancer cell lines. Invest. N. Drugs 32, 783–794 (2014).
Chu, B. et al. ALOX12 is required for p53-mediated tumour suppression through a distinct ferroptosis pathway. Nat. Cell Biol. 21, 579–591 (2019).
Jiang, L. et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature 520, 57–62 (2015).
Badgley, M. A. et al. Cysteine depletion induces pancreatic tumor ferroptosis in mice. Science 368, 85–89 (2020).
Jennis, M. et al. An African-specific polymorphism in the TP53 gene impairs p53 tumor suppressor function in a mouse model. Genes Dev. 30, 918–930 (2016).
Ou, Y., Wang, S. J., Li, D. W., Chu, B. & Gu, W. Activation of SAT1 engages polyamine metabolism with p53-mediated ferroptotic responses. Proc. Natl Acad. Sci. USA 113, E6806–E6812 (2016).
Gao, M. H., Monian, P., Quadri, N., Ramasamy, R. & Jiang, X. J. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell 59, 298–308 (2015).
Tarangelo, A. et al. p53 Suppresses metabolic stress-induced ferroptosis in cancer cells. Cell Rep. 22, 569–575 (2018).
Collisson, E. A. et al. A central role for RAF–>MEK–>ERK signaling in the genesis of pancreatic ductal adenocarcinoma. Cancer Discov. 2, 685–693 (2012).
Bryant, K. L., Mancias, J. D., Kimmelman, A. C. & Der, C. J. KRAS: feeding pancreatic cancer proliferation. Trends Biochem. Sci. 39, 91–100 (2014).
Kang, Y. W. et al. KRAS targeting antibody synergizes anti-cancer activity of gemcitabine against pancreatic cancer. Cancer Lett. 438, 174–186 (2018).
Yang, W. S. & Stockwell, B. R. Synthetic lethal screening identifies compounds activating iron-dependent, nonapoptotic cell death in oncogenic-RAS-harboring cancer cells. Chem. Biol. 15, 234–245 (2008).
Hong, D. S. et al. KRAS(G12C) Inhibition with sotorasib in advanced solid tumors. N. Engl. J. Med. 383, 1207–1217 (2020).
Kamerkar, S. et al. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 546, 498–503 (2017).
Tascilar, M. et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin. Cancer Res. 7, 4115–4121 (2001).
Ellenrieder, V. et al. Transforming growth factor beta1 treatment leads to an epithelial-mesenchymal transdifferentiation of pancreatic cancer cells requiring extracellular signal-regulated kinase 2 activation. Cancer Res. 61, 4222–4228 (2001).
Rowland-Goldsmith, M. A., Maruyama, H., Kusama, T., Ralli, S. & Korc, M. Soluble type II transforming growth factor-β (TGF-β) receptor inhibits TGF-β signaling in COLO-357 pancreatic cancer cells in vitro and attenuates tumor formation. Clin. Cancer Res. 7, 2931–2940 (2001).
Porcelli, L. et al. CAFs and TGF-beta signaling activation by mast cells contribute to resistance to gemcitabine/nabpaclitaxel in pancreatic cancer. Cancers 11, 330 (2019).
Giehl, K., Seidel, B., Gierschik, P., Adler, G. & Menke, A. TGFbeta1 represses proliferation of pancreatic carcinoma cells which correlates with Smad4-independent inhibition of ERK activation. Oncogene 19, 4531–4541 (2000).
David, C. J. et al. TGF-beta tumor suppression through a lethal EMT. Cell 164, 1015–1030 (2016).
Viswanathan, V. S. et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature 547, 453–457 (2017).
Wu, J. et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature 572, 402–406 (2019).
Koong, A. C. et al. Pancreatic tumors show high levels of hypoxia. Int. J. Radiat. Oncol. Biol. Phys. 48, 919–922 (2000).
Carmeliet, P. et al. Role of HIF-1α in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).
Bruick, R. K. Expression of the gene encoding the proapoptotic Nip3 protein is induced by hypoxia. Proc. Natl Acad. Sci. USA 97, 9082–9087 (2000).
Sowter, H. M., Ratcliffe, P. J., Watson, P., Greenberg, A. H. & Harris, A. L. HIF-1-dependent regulation of hypoxic induction of the cell death factors BNIP3 and NIX in human tumors. Cancer Res. 61, 6669–6673 (2001).
Giaccia, A., Siim, B. G. & Johnson, R. S. HIF-1 as a target for drug development. Nat. Rev. Drug Discov. 2, 803–811 (2003).
Akakura, N. et al. Constitutive expression of hypoxia-inducible factor-1alpha renders pancreatic cancer cells resistant to apoptosis induced by hypoxia and nutrient deprivation. Cancer Res. 61, 6548–6554 (2001).
Chen, J. et al. Dominant-negative hypoxia-inducible factor-1 alpha reduces tumorigenicity of pancreatic cancer cells through the suppression of glucose metabolism. Am. J. Pathol. 162, 1283–1291 (2003).
An, W. G. et al. Stabilization of wild-type p53 by hypoxia-inducible factor 1alpha. Nature 392, 405–408 (1998).
Okami, J., Simeone, D. M. & Logsdon, C. D. Silencing of the hypoxia-inducible cell death protein BNIP3 in pancreatic cancer. Cancer Res. 64, 5338–5346 (2004).
Abe, T. et al. Upregulation of BNIP3 by 5-aza-2’-deoxycytidine sensitizes pancreatic cancer cells to hypoxia-mediated cell death. J. Gastroenterol. 40, 504–510 (2005).
Li, C. et al. PINK1 and PARK2 suppress pancreatic tumorigenesis through control of mitochondrial iron-mediated immunometabolism. Dev. Cell 46, 441–455.e8 (2018).
Humpton, T. J. et al. Oncogenic KRAS induces NIX-mediated mitophagy to promote pancreatic cancer. Cancer Discov. 9, 1268–1287 (2019).
Yang, M. et al. Clockophagy is a novel selective autophagy process favoring ferroptosis. Sci. Adv. 5, eaaw2238 (2019).
McKillop, I. H., Girardi, C. A. & Thompson, K. J. Role of fatty acid binding proteins (FABPs) in cancer development and progression. Cell Signal. 62, 109336 (2019).
Sinha, P. et al. Increased expression of epidermal fatty acid binding protein, cofilin, and 14-3-3-sigma (stratifin) detected by two-dimensional gel electrophoresis, mass spectrometry and microsequencing of drug-resistant human adenocarcinoma of the pancreas. Electrophoresis 20, 2952–2960 (1999).
Zou, Y. et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat. Commun. 10, 1617 (2019).
Lee, K. E. et al. Hif1a deletion reveals pro-neoplastic function of B cells in pancreatic neoplasia. Cancer Discov. 6, 256–269 (2016).
Criscimanna, A. et al. PanIN-specific regulation of Wnt signaling by HIF2alpha during early pancreatic tumorigenesis. Cancer Res. 73, 4781–4790 (2013).
Zhao, T. et al. Inhibition of HIF-1α by PX-478 enhances the anti-tumor effect of gemcitabine by inducing immunogenic cell death in pancreatic ductal adenocarcinoma. Oncotarget 6, 2250–2262 (2015).
Schwartz, D. L. et al. Radiosensitization and stromal imaging response correlates for the HIF-1 inhibitor PX-478 given with or without chemotherapy in pancreatic cancer. Mol. Cancer Ther. 9, 2057–2067 (2010).
Qin, C. et al. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Mol. Cancer 19, 50 (2020).
Lim, J. K. M. et al. Cystine/glutamate antiporter xCT (SLC7A11) facilitates oncogenic RAS transformation by preserving intracellular redox balance. Proc. Natl Acad. Sci. USA 116, 9433–9442 (2019).
Hong, Y. B. et al. Nuclear factor (erythroid-derived 2)-like 2 regulates drug resistance in pancreatic cancer cells. Pancreas 39, 463–472 (2010).
Daher, B. et al. Genetic ablation of the cystine transporter xCT in PDAC cells inhibits mTORC1, growth, survival, and tumor formation via nutrient and oxidative stresses. Cancer Res. 79, 3877–3890 (2019).
Wang, L. et al. A pharmacological probe identifies cystathionine beta-synthase as a new negative regulator for ferroptosis. Cell Death Dis. 9, 1005 (2018).
Hayano, M., Yang, W. S., Corn, C. K., Pagano, N. C. & Stockwell, B. R. Loss of cysteinyl-tRNA synthetase (CARS) induces the transsulfuration pathway and inhibits ferroptosis induced by cystine deprivation. Cell Death Differ. 23, 270–278 (2016).
Yang, B. C. & Leung, P. S. Irisin is a positive regulator for ferroptosis in pancreatic cancer. Mol. Ther. Oncolytics 18, 457–466 (2020).
Anandhan, A., Dodson, M., Schmidlin, C. J., Liu, P. & Zhang, D. D. Breakdown of an ironclad defense system: the critical role of NRF2 in mediating ferroptosis. Cell Chem. Biol. 27, 436–447 (2020).
DeNicola, G. M. et al. Oncogene-induced Nrf2 transcription promotes ROS detoxification and tumorigenesis. Nature 475, 106–109 (2011).
Chio, I. I. C. et al. NRF2 Promotes tumor maintenance by modulating mRNA translation in pancreatic cancer. Cell 166, 963–976 (2016).
Lister, A. et al. Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. Mol. Cancer 10, 37 (2011).
Son, J. et al. Glutamine supports pancreatic cancer growth through a KRAS-regulated metabolic pathway. Nature 496, 101–105 (2013).
Bott, A. J. et al. Glutamine anabolism plays a critical role in pancreatic cancer by coupling carbon and nitrogen metabolism. Cell Rep. 29, 1287–1298.e6 (2019).
Chen, R. et al. Disrupting glutamine metabolic pathways to sensitize gemcitabine-resistant pancreatic cancer. Sci. Rep. 7, 7950 (2017).
Mukhopadhyay, S. et al. Undermining glutaminolysis bolsters chemotherapy while NRF2 promotes chemoresistance in KRAS-driven pancreatic cancers. Cancer Res. 80, 1630–1643 (2020).
Schnelldorfer, T. et al. Glutathione depletion causes cell growth inhibition and enhanced apoptosis in pancreatic cancer cells. Cancer 89, 1440–1447 (2000).
Wang, K. et al. Branched-chain amino acid aminotransferase 2 regulates ferroptotic cell death in cancer cells. Cell Death Differ. 28, 1222–1236 (2021).
Shukla, S. K. et al. MUC1 and HIF-1alpha signaling crosstalk induces anabolic glucose metabolism to impart gemcitabine resistance to pancreatic cancer. Cancer Cell 32, 392 (2017).
Lee, H. et al. Energy-stress-mediated AMPK activation inhibits ferroptosis. Nat. Cell Biol. 22, 225–234 (2020).
Song, X. et al. AMPK-mediated BECN1 phosphorylation promotes ferroptosis by directly blocking system Xc- activity. Curr. Biol. 28, 2388–2399.e5 (2018).
Hu, M. et al. AMPK inhibition suppresses the malignant phenotype of pancreatic cancer cells in part by attenuating aerobic glycolysis. J. Cancer 10, 1870–1878 (2019).
Liu, J., Song, N., Huang, Y. & Chen, Y. Irisin inhibits pancreatic cancer cell growth via the AMPK-mTOR pathway. Sci. Rep. 8, 15247 (2018).
Li, J. et al. Regulation and function of autophagy in pancreatic cancer. Autophagy https://doi.org/10.1080/15548627.2020.1847462 (2020).
Piffoux, M., Eriau, E. & Cassier, P. A. Autophagy as a therapeutic target in pancreatic cancer. Br. J. Cancer 124, 333–344 (2021).
Levine, B. & Kroemer, G. Biological functions of autophagy genes: a disease perspective. Cell 176, 11–42 (2019).
Kroemer, G., Marino, G. & Levine, B. Autophagy and the integrated stress response. Mol. Cell 40, 280–293 (2010).
Bai, Y. et al. Lipid storage and lipophagy regulates ferroptosis. Biochem. Biophys. Res. Commun. 508, 997–1003 (2019).
Kinsey, C. G. et al. Protective autophagy elicited by RAF–>MEK–>ERK inhibition suggests a treatment strategy for RAS-driven cancers. Nat. Med. 25, 620–627 (2019).
Liu, J. et al. Autophagy-dependent ferroptosis: machinery and regulation. Cell Chem. Biol. 27, 420–435 (2020).
Wu, Z. et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc. Natl Acad. Sci. USA 116, 2996–3005 (2019).
Mancias, J. D., Wang, X., Gygi, S. P., Harper, J. W. & Kimmelman, A. C. Quantitative proteomics identifies NCOA4 as the cargo receptor mediating ferritinophagy. Nature 509, 105–109 (2014).
Xie, Y., Kuang, F., Liu, J., Tang, D. & Kang, R. DUSP1 blocks autophagy-dependent ferroptosis in pancreatic cancer. J. Pancreatol. 3, 154–160 (2020).
Li, C. et al. Mitochondrial DNA stress triggers autophagy-dependent ferroptotic death. Autophagy 17, 948–960 (2021).
Liu, Y., Wang, Y., Liu, J., Kang, R. & Tang, D. Interplay between MTOR and GPX4 signaling modulates autophagy-dependent ferroptotic cancer cell death. Cancer Gene Ther. 28, 55–63 (2021).
Gao, H. et al. Ferroptosis is a lysosomal cell death process. Biochem. Biophys. Res. Commun. 503, 1550–1556 (2018).
Yamamoto, K. et al. Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I. Nature 581, 100–105 (2020).
Zeh, H. J. et al. A randomized phase II preoperative study of autophagy inhibition with high-dose hydroxychloroquine and gemcitabine/Nab-paclitaxel in pancreatic cancer patients. Clin. Cancer Res. 26, 3126–3134 (2020).
Aghdassi, A. et al. Heat shock protein 70 increases tumorigenicity and inhibits apoptosis in pancreatic adenocarcinoma. Cancer Res. 67, 616–625 (2007).
Mori-Iwamoto, S. et al. Proteomics finding heat shock protein 27 as a biomarker for resistance of pancreatic cancer cells to gemcitabine. Int. J. Oncol. 31, 1345–1350 (2007).
Ghadban, T. et al. HSP90 is a promising target in gemcitabine and 5-fluorouracil resistant pancreatic cancer. Apoptosis 22, 369–380 (2017).
Srinivasan, S. R. et al. Heat shock protein 70 (Hsp70) suppresses RIP1-dependent apoptotic and necroptotic cascades. Mol. Cancer Res. 16, 58–68 (2018).
Weinberg, F. et al. Mitochondrial metabolism and ROS generation are essential for Kras-mediated tumorigenicity. Proc. Natl Acad. Sci. USA 107, 8788–8793 (2010).
Storz, P. KRas, ROS and the initiation of pancreatic cancer. Small GTPases 8, 38–42 (2017).
Hingorani, S. R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).
Leinwand, J. & Miller, G. Regulation and modulation of antitumor immunity in pancreatic cancer. Nat. Immunol. 21, 1152–1159 (2020).
Lowenfels, A. B. et al. Pancreatitis and the risk of pancreatic cancer. International Pancreatitis Study Group. N. Engl. J. Med. 328, 1433–1437 (1993).
Carriere, C., Young, A. L., Gunn, J. R., Longnecker, D. S. & Korc, M. Acute pancreatitis markedly accelerates pancreatic cancer progression in mice expressing oncogenic Kras. Biochem. Biophys. Res. Commun. 382, 561–565 (2009).
Philip, B. et al. A high-fat diet activates oncogenic Kras and COX2 to induce development of pancreatic ductal adenocarcinoma in mice. Gastroenterology 145, 1449–1458 (2013).
Guerra, C. et al. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell 11, 291–302 (2007).
Pushalkar, S. et al. The pancreatic cancer microbiome promotes oncogenesis by induction of innate and adaptive immune suppression. Cancer Discov. 8, 403–416 (2018).
Riquelme, E. et al. Tumor microbiome diversity and composition influence pancreatic cancer outcomes. Cell 178, 795–806.e12 (2019).
Aykut, B. et al. The fungal mycobiome promotes pancreatic oncogenesis via activation of MBL. Nature 574, 264–267 (2019).
Nejman, D. et al. The human tumor microbiome is composed of tumor type-specific intracellular bacteria. Science 368, 973–980 (2020).
Sendler, M. et al. NLRP3 inflammasome regulates development of systemic inflammatory response and compensatory anti-inflammatory response syndromes in mice with acute pancreatitis. Gastroenterology 158, 253–269.e14 (2020).
Liu, Y., Wang, Y., Liu, J., Kang, R. & Tang, D. The circadian clock protects against ferroptosis-induced sterile inflammation. Biochem. Biophys. Res. Commun. 525, 620–625 (2020).
Seifert, L. et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature 532, 245–249 (2016).
Ando, Y. et al. Necroptosis in pancreatic cancer promotes cancer cell migration and invasion by release of CXCL5. PLoS One 15, e0228015 (2020).
Wang, W. et al. RIP1 kinase drives macrophage-mediated adaptive immune tolerance in pancreatic cancer. Cancer Cell 34, 757–774.e7 (2018).
Colbert, L. E. et al. Pronecrotic mixed lineage kinase domain-like protein expression is a prognostic biomarker in patients with early-stage resected pancreatic adenocarcinoma. Cancer 119, 3148–3155 (2013).
Dai, E. et al. Ferroptotic damage promotes pancreatic tumorigenesis through a TMEM173/STING-dependent DNA sensor pathway. Nat. Commun. 11, 6339 (2020).
Fang, X. et al. The HMGB1-AGER-STING1 pathway mediates the sterile inflammatory response to alkaliptosis. Biochem. Biophys. Res. Commun. 560, 165–171 (2021).
Dai, E. et al. Autophagy-dependent ferroptosis drives tumor-associated macrophage polarization via release and uptake of oncogenic KRAS protein. Autophagy 16, 2069–2083 (2020).
Das, S., Shapiro, B., Vucic, E. A., Vogt, S. & Bar-Sagi, D. Tumor cell-derived IL1beta promotes desmoplasia and immune suppression in pancreatic cancer. Cancer Res. 80, 1088–1101 (2020).
Daley, D. et al. NLRP3 signaling drives macrophage-induced adaptive immune suppression in pancreatic carcinoma. J. Exp. Med. 214, 1711–1724 (2017).
Chen, X., Yu, C., Kang, R., Kroemer, G. & Tang, D. Cellular degradation systems in ferroptosis. Cell Death Differ. 28, 1135–1148 (2021).
Rosenfeldt, M. T. et al. p53 status determines the role of autophagy in pancreatic tumour development. Nature 504, 296–300 (2013).
Efimova, I. et al. Vaccination with early ferroptotic cancer cells induces efficient antitumor immunity. J. Immunother. Cancer 8, e001369 (2020).
Ansari, D., Gustafsson, A. & Andersson, R. Update on the management of pancreatic cancer: surgery is not enough. World J. Gastroenterol. 21, 3157–3165 (2015).
Plunkett, W. et al. Gemcitabine: metabolism, mechanisms of action, and self-potentiation. Semin. Oncol. 22, 3–10 (1995).
Conroy, T. et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N. Engl. J. Med. 364, 1817–1825 (2011).
Von Hoff, D. D. et al. Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine. N. Engl. J. Med. 369, 1691–1703 (2013).
Modi, S., Kir, D., Banerjee, S. & Saluja, A. Control of apoptosis in treatment and biology of pancreatic cancer. J. Cell Biochem. 117, 279–288 (2016).
Geller, L. T. et al. Potential role of intratumor bacteria in mediating tumor resistance to the chemotherapeutic drug gemcitabine. Science 357, 1156–1160 (2017).
Philippou, Y., Sjoberg, H., Lamb, A. D., Camilleri, P. & Bryant, R. J. Harnessing the potential of multimodal radiotherapy in prostate cancer. Nat. Rev. Urol. 17, 321–338 (2020).
Lang, X. et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov. 9, 1673–1685 (2019).
Cao, J. Y. et al. A genome-wide haploid genetic screen identifies regulators of glutathione abundance and ferroptosis sensitivity. Cell Rep. 26, 1544–1556.e8 (2019).
Xiao, J. et al. Radiation causes tissue damage by dysregulating inflammasome-gasdermin D signaling in both host and transplanted cells. PLoS Biol. 18, e3000807 (2020).
Chen, X. et al. Toll-like receptor 2 and Toll-like receptor 4 exhibit distinct regulation of cancer cell stemness mediated by cell death-induced high-mobility group Box 1. EBioMedicine 40, 135–150 (2019).
Golan, T. et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381, 317–327 (2019).
Iqbal, J. et al. The incidence of pancreatic cancer in BRCA1 and BRCA2 mutation carriers. Br. J. Cancer 107, 2005–2009 (2012).
Barbie, D. A. et al. Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1. Nature 462, 108–112 (2009).
Scholl, C. et al. Synthetic lethal interaction between oncogenic KRAS dependency and STK33 suppression in human cancer cells. Cell 137, 821–834 (2009).
Steckel, M. et al. Determination of synthetic lethal interactions in KRAS oncogene-dependent cancer cells reveals novel therapeutic targeting strategies. Cell Res. 22, 1227–1245 (2012).
Yamaguchi, Y., Kasukabe, T. & Kumakura, S. Piperlongumine rapidly induces the death of human pancreatic cancer cells mainly through the induction of ferroptosis. Int. J. Oncol. 52, 1011–1022 (2018).
Chen, X., Kang, R., Kroemer, G. & Tang, D. Ferroptosis in infection, inflammation, and immunity. J. Exp. Med. 218, e20210518 (2021).
Hu, N. et al. Pirin is a nuclear redox-sensitive modulator of autophagy-dependent ferroptosis. Biochem. Biophys. Res. Commun. 536, 100–106 (2021).
Liu, L. et al. NUPR1 is a critical repressor of ferroptosis. Nat. Commun. 12, 647 (2021).
Kuang, F., Liu, J., Xie, Y., Tang, D. & Kang, R. MGST1 is a redox-sensitive repressor of ferroptosis in pancreatic cancer cells. Cell Chem. Biol. 28, 765–775.e5 (2021).
Akimoto, M., Maruyama, R., Kawabata, Y., Tajima, Y. & Takenaga, K. Antidiabetic adiponectin receptor agonist AdipoRon suppresses tumour growth of pancreatic cancer by inducing RIPK1/ERK-dependent necroptosis. Cell Death Dis. 9, 804 (2018).
Santofimia-Castano, P. et al. Ligand-based design identifies a potent NUPR1 inhibitor exerting anticancer activity via necroptosis. J. Clin. Invest. 129, 2500–2513 (2019).
Galluzzi, L., Humeau, J., Buque, A., Zitvogel, L. & Kroemer, G. Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors. Nat. Rev. Clin. Oncol. 17, 725–741 (2020).
Torphy, R. J., Zhu, Y. & Schulick, R. D. Immunotherapy for pancreatic cancer: barriers and breakthroughs. Ann. Gastroenterol. Surg. 2, 274–281 (2018).
O’Donnell, J. S., Teng, M. W. L. & Smyth, M. J. Cancer immunoediting and resistance to T cell-based immunotherapy. Nat. Rev. Clin. Oncol. 16, 151–167 (2019).
Clark, C. E. et al. Dynamics of the immune reaction to pancreatic cancer from inception to invasion. Cancer Res. 67, 9518–9527 (2007).
Bear, A. S., Vonderheide, R. H. & O’Hara, M. H. Challenges and opportunities for pancreatic cancer immunotherapy. Cancer Cell 38, 788–802 (2020).
Moral, J. A. et al. ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity. Nature 579, 130–135 (2020).
Huang, J. et al. CDK1/2/5 inhibition overcomes IFNG-mediated adaptive immune resistance in pancreatic cancer. Gut 70, 890–899 (2021).
Galluzzi, L. et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J. Immunother. Cancer 8, e000337 (2020).
Angelova, A. L. et al. Complementary induction of immunogenic cell death by oncolytic parvovirus H-1PV and gemcitabine in pancreatic cancer. J. Virol. 88, 5263–5276 (2014).
Lu, J. et al. Nano-enabled pancreas cancer immunotherapy using immunogenic cell death and reversing immunosuppression. Nat. Commun. 8, 1811 (2017).
Duewell, P. et al. RIG-I-like helicases induce immunogenic cell death of pancreatic cancer cells and sensitize tumors toward killing by CD8+ T cells. Cell Death Differ. 21, 1825–1837 (2014).
Ye, J. et al. Assessing the magnitude of immunogenic cell death following chemotherapy and irradiation reveals a new strategy to treat pancreatic cancer. Cancer Immunol. Res. 8, 94–107 (2020).
Wang, W. et al. CD8+ T cells regulate tumour ferroptosis during cancer immunotherapy. Nature 569, 270–274 (2019).
Wang, Q. et al. A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature 579, 421–426 (2020).
Zhang, Z. et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature 579, 415–420 (2020).
Yang, M. et al. TFAM is a novel mediator of immunogenic cancer cell death. Oncoimmunology 7, e1431086 (2018).
Newton, K. et al. Activity of protein kinase RIPK3 determines whether cells die by necroptosis or apoptosis. Science 343, 1357–1360 (2014).
Buchbinder, J. H., Pischel, D., Sundmacher, K., Flassig, R. J. & Lavrik, I. N. Quantitative single cell analysis uncovers the life/death decision in CD95 network. PLoS Comput. Biol. 14, e1006368 (2018).
Krysko, D. V. et al. Immunogenic cell death and DAMPs in cancer therapy. Nat. Rev. Cancer 12, 860–875 (2012).
Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).
Hou, W. et al. Strange attractors: DAMPs and autophagy link tumor cell death and immunity. Cell Death Dis. 4, e966 (2013).
Dey, P. et al. Oncogenic KRAS-driven metabolic reprogramming in pancreatic cancer cells utilizes cytokines from the tumor microenvironment. Cancer Discov. 10, 608–625 (2020).
Markosyan, N. et al. Tumor cell-intrinsic EPHA2 suppresses anti-tumor immunity by regulating PTGS2 (COX-2). J. Clin. Invest. 129, 3594–3609 (2019).
Zhang, Y. et al. Regulatory T-cell depletion alters the tumor microenvironment and accelerates pancreatic carcinogenesis. Cancer Discov. 10, 422–439 (2020).
Daley, D. et al. T cells support pancreatic oncogenesis by restraining αβ T cell activation. Cell 166, 1485–1499.e15 (2016).
Bayne, L. J. et al. Tumor-derived granulocyte-macrophage colony-stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer. Cancer Cell 21, 822–835 (2012).
Daley, D. et al. Dectin 1 activation on macrophages by galectin 9 promotes pancreatic carcinoma and peritumoral immune tolerance. Nat. Med. 23, 556–567 (2017).
Hegde, S. et al. Dendritic cell paucity leads to dysfunctional immune surveillance in pancreatic cancer. Cancer Cell 37, 289–307.e9 (2020).
Beatty, G. L. et al. CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans. Science 331, 1612–1616 (2011).
Gunderson, A. J. et al. Bruton tyrosine kinase-dependent immune cell cross-talk drives pancreas cancer. Cancer Discov. 6, 270–285 (2016).
Tape, C. J. et al. Oncogenic KRAS regulates tumor cell signaling via stromal reciprocation. Cell 165, 910–920 (2016).
Lesina, M. et al. Stat3/Socs3 activation by IL-6 transsignaling promotes progression of pancreatic intraepithelial neoplasia and development of pancreatic cancer. Cancer Cell 19, 456–469 (2011).
Chen, X., Comish, P., Tang, D. & Kang, R. Characteristics and biomarkers of ferroptosis. Front. Cell Dev. Biol. 9, 637162 (2021).
Tang, D., Kang, R., Coyne, C. B., Zeh, H. J. & Lotze, M. T. PAMPs and DAMPs: signal 0s that spur autophagy and immunity. Immunol. Rev. 249, 158–175 (2012).
Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).
Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).
Vacchelli, E. et al. Chemotherapy-induced antitumor immunity requires formyl peptide receptor 1. Science 350, 972–978 (2015).
Apetoh, L. et al. Toll-like receptor 4-dependent contribution of the immune system to anticancer chemotherapy and radiotherapy. Nat. Med. 13, 1050–1059 (2007).
Garg, A. D. et al. Pathogen response-like recruitment and activation of neutrophils by sterile immunogenic dying cells drives neutrophil-mediated residual cell killing. Cell Death Differ. 24, 832–843 (2017).
Chiba, S. et al. Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 13, 832–842 (2012).
Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).
Panaretakis, T. et al. The co-translocation of ERp57 and calreticulin determines the immunogenicity of cell death. Cell Death Differ. 15, 1499–1509 (2008).
Fucikova, J. et al. Human tumor cells killed by anthracyclines induce a tumor-specific immune response. Cancer Res. 71, 4821–4833 (2011).
We thank Dave Primm (Department of Surgery, University of Texas Southwestern Medical Center) for his critical reading of the manuscript. G.K. is supported by the Ligue Contre le Cancer (Equipe Labellisée); Agence National de la Recherche (ANR) – Projets blancs; ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases; Association pour la recherche sur le cancer; Cancéropôle Ile-de-France; Chancelerie des Universités de Paris (Legs Poix), Fondation pour la Recherche Médicale; a donation by Elior; European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR); Gustave Roussy Odyssea, the European Union Horizon 2020 Project Oncobiome; Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Institut National du Cancer; Inserm (HTE); Institut Universitaire de France; LeDucq Foundation; the LabEx Immuno-Oncology; the RHU Torino Lumière; the Seerave Foundation; the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE); and the SIRIC Cancer Research and Personalized Medicine Program (CARPEM).
The authors declare no competing interests.
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Chen, X., Zeh, H.J., Kang, R. et al. Cell death in pancreatic cancer: from pathogenesis to therapy. Nat Rev Gastroenterol Hepatol (2021). https://doi.org/10.1038/s41575-021-00486-6