Many cancer therapies aim to trigger apoptosis in cancer cells. Nevertheless, the presence of oncogenic alterations in these cells and distorted composition of tumour microenvironment largely limit the clinical efficacy of this type of therapy. Luckily, scientific consensus describes about 10 different cell death subroutines with different regulatory pathways and cancer cells are probably not able to avoid all of cell death types at once. Therefore, a focused and individualised therapy is needed to address the specific advantages and disadvantages of individual tumours. Although much is known about apoptosis, therapeutic opportunities of other cell death pathways are often neglected. Molecular heterogeneity of head and neck squamous cell carcinomas (HNSCC) causing unpredictability of the clinical response represents a grave challenge for oncologists and seems to be a critical component of treatment response. The large proportion of this clinical heterogeneity probably lies in alterations of cell death pathways. How exactly cells die is very important because the predominant type of cell death can have multiple impacts on the therapeutic response as cell death itself acts as a second messenger. In this review, we discuss the different types of programmed cell death (PCD), their connection with HNSCC pathogenesis and possible therapeutic windows that result from specific sensitivity to some form of PCD in some clinically relevant subgroups of HNSCC.

BIOCEV 1st Faculty of Medicine Charles University Prumyslova 595 CZ 252 50 Vestec Czech Republic

Department of Chemistry and Biochemistry Mendel University in Brno Zemedelska 1 CZ 613 00 Brno Czech Republic

Department of Pathological Physiology Faculty of Medicine Masaryk University Kamenice 5 CZ 625 00 Brno Czech Republic

Department of Physiology Faculty of Medicine Masaryk University Kamenice 5 CZ 625 00 Brno Czech Republic

See more in PubMed

Lemaire F, et al. Differential expression profiling of head and neck squamous cell carcinoma (HNSCC) Br. J. Cancer. 2003;89:1940–1949. doi: 10.1038/sj.bjc.6601373. PubMed DOI PMC

Koch WM, Ridge JA, Forastiere A, Manola J. Comparison of clinical and pathological staging in head and neck squamous cell carcinoma: results from Intergroup Study ECOG 4393/RTOG 9614. Arch. Otolaryngol. Head. Neck Surg. 2009;135:851–858. doi: 10.1001/archoto.2009.123. PubMed DOI PMC

Keck MK, et al. Integrative analysis of head and neck cancer identifies two biologically distinct HPV and three non-HPV subtypes. Clin. Cancer Res. 2015;21:870–881. doi: 10.1158/1078-0432.CCR-14-2481. PubMed DOI

Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat. Rev. Cancer. 2018;18:269–282. doi: 10.1038/nrc.2018.11. PubMed DOI

Wallace NA, Galloway DA. Manipulation of cellular DNA damage repair machinery facilitates propagation of human papillomaviruses. Semin. cancer Biol. 2014;26:30–42. doi: 10.1016/j.semcancer.2013.12.003. PubMed DOI PMC

Garnett TO, Duerksen-Hughes PJ. Modulation of apoptosis by human papillomavirus (HPV) oncoproteins. Arch. Virol. 2006;151:2321–2335. doi: 10.1007/s00705-006-0821-0. PubMed DOI PMC

Legrand AJ, Konstantinou M, Goode EF, Meier P. The diversification of cell death and immunity: memento mori. Mol. Cell. 2019;76:232–242. doi: 10.1016/j.molcel.2019.09.006. PubMed DOI

Galluzzi L, et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on cell death 2018. Cell Death Differ. 2018;25:486–541. doi: 10.1038/s41418-017-0012-4. PubMed DOI PMC

Giampazolias E, et al. Mitochondrial permeabilization engages NF-kappaB-dependent anti-tumour activity under caspase deficiency. Nat. Cell Biol. 2017;19:1116–1129. doi: 10.1038/ncb3596. PubMed DOI PMC

Rongvaux A, et al. Apoptotic caspases prevent the induction of type I interferons by mitochondrial DNA. Cell. 2014;159:1563–1577. doi: 10.1016/j.cell.2014.11.037. PubMed DOI PMC

Shaikh MH, Bortnik V, McMillan NAJ, Idris A. cGAS-STING responses are dampened in high-risk HPV type 16 positive head and neck squamous cell carcinoma cells. Microb. Pathog. 2019;132:162–165. doi: 10.1016/j.micpath.2019.05.004. PubMed DOI

Andersen AS, Koldjaer Sølling AS, Ovesen T, Rusan M. The interplay between HPV and host immunity in head and neck squamous cell carcinoma. Int. J. Cancer. 2014;134:2755–2763. doi: 10.1002/ijc.28411. PubMed DOI

Thomas M, Banks L. Human papillomavirus (HPV) E6 interactions with Bak are conserved amongst E6 proteins from high and low risk HPV types. J. Gen. Virol. 1999;80:1513–1517. doi: 10.1099/0022-1317-80-6-1513. PubMed DOI

Kimple RJ, et al. Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res. 2013;73:4791–4800. doi: 10.1158/0008-5472.CAN-13-0587. PubMed DOI PMC

Maruyama H, et al. Human papillomavirus and p53 mutations in head and neck squamous cell carcinoma among Japanese population. Cancer Sci. 2014;105:409–417. doi: 10.1111/cas.12369. PubMed DOI PMC

Nakahara T, et al. Activation of NF-κB by human papillomavirus 16 E1 limits E1-dependent viral replication through degradation of E1. J. Virol. 2015;89:5040–5059. doi: 10.1128/JVI.00389-15. PubMed DOI PMC

Almeida L., et al. NF kappa B mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC). FEBS Open Bio.4, (2013) PubMed PMC

Liu S, et al. Stabilization of slug by NF-kappaB is essential for TNF-alpha -induced migration and epithelial-mesenchymal transition in head and neck squamous cell carcinoma cells. Cell Physiol. Biochem. 2018;47:567–578. doi: 10.1159/000489990. PubMed DOI

Boaru S. et al. NLRP3 inflammasome expression is driven by NF-κB in cultured hepatocytes. Biochem. Biophys. Res. Commun. 458, 700–706 (2015). PubMed

Bauernfeind FG, et al. Cutting edge: NF-kappaB activating pattern recognition and cytokine receptors license NLRP3 inflammasome activation by regulating NLRP3 expression. J. Immunol. 2009;183:787–791. doi: 10.4049/jimmunol.0901363. PubMed DOI PMC

Galluzzi L, Yamazaki T, Kroemer G. Linking cellular stress responses to systemic homeostasis. Nat. Rev. Mol. Cell Biol. 2018;19:731–745. doi: 10.1038/s41580-018-0068-0. PubMed DOI

Wang J, et al. HPV-positive status associated with inflamed immune microenvironment and improved response to anti-PD-1 therapy in head and neck squamous cell carcinoma. Sci. Rep. 2019;9:13404. doi: 10.1038/s41598-019-49771-0. PubMed DOI PMC

Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat. Rev. Cancer. 2012;12:298–306. doi: 10.1038/nrc3245. PubMed DOI

Badoual C, et al. PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV-associated head and neck cancer. Cancer Res. 2013;73:128–138. doi: 10.1158/0008-5472.CAN-12-2606. PubMed DOI

Park JW, et al. Human papillomavirus type 16 E7 oncoprotein causes a delay in repair of DNA damage. Radiother. Oncol. 2014;113:337–344. doi: 10.1016/j.radonc.2014.08.026. PubMed DOI PMC

Rieckmann T, et al. HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother. Oncol. 2013;107:242–246. doi: 10.1016/j.radonc.2013.03.013. PubMed DOI

Vermeer DW, et al. Radiation-induced loss of cell surface CD47 enhances immune-mediated clearance of human papillomavirus-positive cancer. Int. J. Cancer. 2013;133:120–129. doi: 10.1002/ijc.28015. PubMed DOI PMC

Gasser S, Orsulic S, Brown EJ, Raulet DH. The DNA damage pathway regulates innate immune system ligands of the NKG2D receptor. Nature. 2005;436:1186–1190. doi: 10.1038/nature03884. PubMed DOI PMC

Sayitoglu E. C. et al. Boosting natural killer cell-mediated targeting of sarcoma through DNAM-1 and NKG2D. Front. Immunol.11, 40 (2020). PubMed PMC

Lopez-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control of metastasis by NK cells. Cancer Cell. 2017;32:135–154. doi: 10.1016/j.ccell.2017.06.009. PubMed DOI

Raj K, Berguerand S, Southern S, Doorbar J, Beard P. E1 empty set E4 protein of human papillomavirus type 16 associates with mitochondria. J. Virol. 2004;78:7199–7207. doi: 10.1128/JVI.78.13.7199-7207.2004. PubMed DOI PMC

Buckley L, Jackett L, Clark J, Gupta R. HPV-related oropharyngeal carcinoma: a review of clinical and pathologic features with emphasis on updates in clinical and pathologic staging. Adv. Anat. Pathol. 2018;25:180–188. doi: 10.1097/PAP.0000000000000179. PubMed DOI

Elrefaey S, Massaro MA, Chiocca S, Chiesa F, Ansarin M. HPV in oropharyngeal cancer: the basics to know in clinical practice. Acta Otorhinolaryngol. Ital. 2014;34:299–309. PubMed PMC

Lawrence MS, et al. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517:576–582. doi: 10.1038/nature14129. PubMed DOI PMC

Walter V, et al. Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes. PloS ONE. 2013;8:e56823. doi: 10.1371/journal.pone.0056823. PubMed DOI PMC

Lim SC, Parajuli KR, Han SI. Keratin 6, induced by chronic cisplatin exposure, confers chemoresistance in human gastric carcinoma cells. Oncol. Rep. 2019;42:797–804. PubMed

Jung YS, et al. HPV-associated differential regulation of tumor metabolism in oropharyngeal head and neck cancer. Oncotarget. 2017;8:51530–51541. doi: 10.18632/oncotarget.17887. PubMed DOI PMC

Puzio-Kuter AM. The role of p53 in metabolic regulation. Genes Cancer. 2011;2:385–391. doi: 10.1177/1947601911409738. PubMed DOI PMC

Cruz-Gregorio A, et al. E6 oncoproteins from high-risk human papillomavirus induce mitochondrial metabolism in a head and neck squamous cell carcinoma model. Biomolecules. 2019;9:351. doi: 10.3390/biom9080351. PubMed DOI PMC

Sandulache VC, et al. Individualizing antimetabolic treatment strategies for head and neck squamous cell carcinoma based on TP53 mutational status. Cancer. 2012;118:711–721. doi: 10.1002/cncr.26321. PubMed DOI PMC

Thomas RJ, et al. HPV/E7 induces chemotherapy-mediated tumor suppression by ceramide-dependent mitophagy. EMBO Mol. Med. 2017;9:1030–1051. doi: 10.15252/emmm.201607088. PubMed DOI PMC

Yang Z, et al. Cisplatin preferentially binds mitochondrial DNA and voltage-dependent anion channel protein in the mitochondrial membrane of head and neck squamous cell carcinoma: possible role in apoptosis. Clin. Cancer Res. 2006;12:5817–5825. doi: 10.1158/1078-0432.CCR-06-1037. PubMed DOI

Leonard BC, Johnson DE. Signaling by cell surface death receptors: alterations in head and neck cancer. Adv. Biol. Regul. 2018;67:170–178. doi: 10.1016/j.jbior.2017.10.006. PubMed DOI PMC

Grunert M, et al. The adaptor protein FADD and the initiator caspase-8 mediate activation of NF-κB by TRAIL. Cell Death Dis. 2012;3:e414–e414. doi: 10.1038/cddis.2012.154. PubMed DOI PMC

Kabsch K, Alonso A. The human papillomavirus type 16 E5 protein impairs TRAIL- and FasL-mediated apoptosis in HaCaT cells by different mechanisms. J. Virol. 2002;76:12162–12172. doi: 10.1128/JVI.76.23.12162-12172.2002. PubMed DOI PMC

Filippova M, Parkhurst L, Duerksen-Hughes PJ. The human papillomavirus 16 E6 protein binds to Fas-associated death domain and protects cells from Fas-triggered apoptosis. J. Biol. Chem. 2004;279:25729–25744. doi: 10.1074/jbc.M401172200. PubMed DOI

Duerksen-Hughes PJ, Yang J, Schwartz SB. HPV 16 E6 blocks TNF-mediated apoptosis in mouse fibroblast LM cells. Virology. 1999;264:55–65. doi: 10.1006/viro.1999.9977. PubMed DOI

Lagunas-Martínez A, Madrid-Marina V, Gariglio P. Modulation of apoptosis by early human papillomavirus proteins in cervical cancer. Biochimica et Biophysica Acta. Cancer. 2010;1805:6–16. PubMed

Garnett TO, Filippova M, Duerksen-Hughes PJ. Accelerated degradation of FADD and procaspase 8 in cells expressing human papilloma virus 16 E6 impairs TRAIL-mediated apoptosis. Cell Death Differ. 2006;13:1915–1926. doi: 10.1038/sj.cdd.4401886. PubMed DOI PMC

Yuan H, et al. Human papillomavirus type 16 E6 and E7 oncoproteins upregulate c-IAP2 gene expression and confer resistance to apoptosis. Oncogene. 2005;24:5069–5078. doi: 10.1038/sj.onc.1208691. PubMed DOI

Stöppler H, et al. The E7 protein of human papillomavirus type 16 sensitizes primary human keratinocytes to apoptosis. Oncogene. 1998;17:1207–1214. doi: 10.1038/sj.onc.1202053. PubMed DOI

Lai D, et al. Localization of HPV-18 E2 at mitochondrial membranes induces ROS release and modulates host cell metabolism. PloS ONE. 2013;8:e75625. doi: 10.1371/journal.pone.0075625. PubMed DOI PMC

Anayannis NV, et al. Association of an intact E2 gene with higher HPV viral load, higher viral oncogene expression, and improved clinical outcome in HPV16 positive head and neck squamous cell carcinoma. PloS ONE. 2018;13:e0191581–e0191581. doi: 10.1371/journal.pone.0191581. PubMed DOI PMC

Demeret C, Garcia-Carranca A, Thierry F. Transcription-independent triggering of the extrinsic pathway of apoptosis by human papillomavirus 18 E2 protein. Oncogene. 2003;22:168–175. doi: 10.1038/sj.onc.1206108. PubMed DOI

Webster K, et al. The human papillomavirus (HPV) 16 E2 protein induces apoptosis in the absence of other HPV proteins and via a p53-dependent pathway. J. Biol. Chem. 2000;275:87–94. doi: 10.1074/jbc.275.1.87. PubMed DOI

Gross-Mesilaty S, et al. Basal and human papillomavirus E6 oncoprotein-induced degradation of Myc proteins by the ubiquitin pathway. Proc. Natl Acad. Sci. USA. 1998;95:8058–8063. doi: 10.1073/pnas.95.14.8058. PubMed DOI PMC

Ko A, et al. Oncogene-induced senescence mediated by c-Myc requires USP10 dependent deubiquitination and stabilization of p14ARF. Cell Death. Differ. 2018;25:1050–1062. PubMed PMC

Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333:1157–1160. doi: 10.1126/science.1208130. PubMed DOI PMC

Broniarczyk J, Ring N, Massimi P, Giacca M, Banks L. HPV-16 virions can remain infectious for 2 weeks on senescent cells but require cell cycle re-activation to allow virus entry. Sci. Rep. 2018;8:811. doi: 10.1038/s41598-017-18809-6. PubMed DOI PMC

Duray A, et al. Human papillomavirus DNA strongly correlates with a poorer prognosis in oral cavity carcinoma. Laryngoscope. 2012;122:1558–1565. doi: 10.1002/lary.23298. PubMed DOI

Chen WS, et al. CDKN2A copy number loss is an independent prognostic factor in HPV-negative head and neck squamous cell carcinoma. Front. Oncol. 2018;8:95. doi: 10.3389/fonc.2018.00095. PubMed DOI PMC

Tsapras P, Nezis IP. Caspase involvement in autophagy. Cell Death Differ. 2017;24:1369–1379. doi: 10.1038/cdd.2017.43. PubMed DOI PMC

Wirawan E, et al. Caspase-mediated cleavage of Beclin-1 inactivates Beclin-1-induced autophagy and enhances apoptosis by promoting the release of proapoptotic factors from mitochondria. Cell Death Dis. 2010;1:e18. doi: 10.1038/cddis.2009.16. PubMed DOI PMC

Furuya D, Tsuji N, Yagihashi A, Watanabe N. Beclin 1 augmented cis-diamminedichloroplatinum induced apoptosis via enhancing caspase-9 activity. Exp. Cell Res. 2005;307:26–40. doi: 10.1016/j.yexcr.2005.02.023. PubMed DOI

Young MM, et al. Autophagosomal membrane serves as platform for intracellular death-inducing signaling complex (iDISC)-mediated caspase-8 activation and apoptosis. J. Biol. Chem. 2012;287:12455–12468. doi: 10.1074/jbc.M111.309104. PubMed DOI PMC

Hughes MA, et al. Co-operative and hierarchical binding of c-FLIP and caspase-8: a unified model defines how c-FLIP isoforms differentially control cell fate. Mol. Cell. 2016;61:834–849. doi: 10.1016/j.molcel.2016.02.023. PubMed DOI PMC

Li X, et al. Overexpression of cFLIP in head and neck squamous cell carcinoma and its clinicopathologic correlations. J. Cancer Res. Clin. Oncol. 2008;134:609–615. doi: 10.1007/s00432-007-0325-7. PubMed DOI

Rubinstein AD, Eisenstein M, Ber Y, Bialik S, Kimchi A. The autophagy protein Atg12 associates with antiapoptotic Bcl-2 family members to promote mitochondrial apoptosis. Mol. Cell. 2011;44:698–709. doi: 10.1016/j.molcel.2011.10.014. PubMed DOI

Radoshevich L, et al. ATG12 conjugation to ATG3 regulates mitochondrial homeostasis and cell death. Cell. 2010;142:590–600. doi: 10.1016/j.cell.2010.07.018. PubMed DOI PMC

Lindqvist LM, et al. Autophagy induced during apoptosis degrades mitochondria and inhibits type I interferon secretion. Cell Death Differ. 2018;25:784–796. doi: 10.1038/s41418-017-0017-z. PubMed DOI PMC

McCormick KD, et al. Innate immune signaling through differential RIPK1 expression promote tumor progression in head and neck squamous cell carcinoma. Carcinogenesis. 2016;37:522–529. doi: 10.1093/carcin/bgw032. PubMed DOI PMC

Shi F, et al. EBV(LMP1)-induced metabolic reprogramming inhibits necroptosis through the hypermethylation of the RIP3 promoter. Theranostics. 2019;9:2424–2438. doi: 10.7150/thno.30941. PubMed DOI PMC

O’Donnell MA, et al. Caspase 8 inhibits programmed necrosis by processing CYLD. Nat. Cell Biol. 2011;13:1437–1442. doi: 10.1038/ncb2362. PubMed DOI PMC

Beck T. N. & Golemis E. A. Genomic insights into head and neck cancer. Cancers Head Neck. 1, 1 (2016). PubMed PMC

Moody CA, Fradet-Turcotte A, Archambault J, Laimins LA. Human papillomaviruses activate caspases upon epithelial differentiation to induce viral genome amplification. Proc. Natl Acad. Sci. USA. 2007;104:19541–19546. doi: 10.1073/pnas.0707947104. PubMed DOI PMC

Manzo-Merino J, Massimi P, Lizano M, Banks L. The human papillomavirus (HPV) E6 oncoproteins promotes nuclear localization of active caspase 8. Virology. 2014;450–451:146–152. doi: 10.1016/j.virol.2013.12.013. PubMed DOI

Aréchaga-Ocampo E, et al. HPV+ cervical carcinomas and cell lines display altered expression of caspases. Gynecologic Oncol. 2008;108:10–18. doi: 10.1016/j.ygyno.2007.08.070. PubMed DOI

Newton K, et al. Cleavage of RIPK1 by caspase-8 is crucial for limiting apoptosis and necroptosis. Nature. 2019;574:428–431. doi: 10.1038/s41586-019-1548-x. PubMed DOI

Ma W, et al. Human papillomavirus downregulates the expression of IFITM1 and RIPK3 to escape from IFNγ- and TNFα-mediated antiproliferative effects and necroptosis. Front. Immunol. 2016;7:496. PubMed PMC

Hammon RJ, Michaud WA, Rocco JW. Status of the intrinsic and extrinsic apoptotic pathways in HNSCC and impact on sensitivity to etoposide-, TRAIL-, and Cisplatin-induced cell death: molecular biology and therapeutics. Int. J. Radiat. Oncol., Biol., Phys. 2014;88:515. doi: 10.1016/j.ijrobp.2013.11.163. DOI

Jackson-Bernitsas DG, et al. Evidence that TNF-TNFR1-TRADD-TRAF2-RIP-TAK1-IKK pathway mediates constitutive NF-kappaB activation and proliferation in human head and neck squamous cell carcinoma. Oncogene. 2007;26:1385–1397. doi: 10.1038/sj.onc.1209945. PubMed DOI

Li J, et al. Necroptosis in head and neck squamous cell carcinoma: characterization of clinicopathological relevance and in vitro cell model. Cell Death Dis. 2020;11:391. doi: 10.1038/s41419-020-2538-5. PubMed DOI PMC

Gaiotti D, et al. Tumor necrosis factor-alpha promotes human papillomavirus (HPV) E6/E7 RNA expression and cyclin-dependent kinase activity in HPV-immortalized keratinocytes by a ras-dependent pathway. Mol. Carcinog. 2000;27:97–109. doi: 10.1002/(SICI)1098-2744(200002)27:2<97::AID-MC5>3.0.CO;2-V. PubMed DOI

Uzunparmak, B. et al. Caspase-8 loss radiosensitizes head and neck squamous cell carcinoma to SMAC mimetic-induced necroptosis. JCI Insight.5, e139837 (2020). PubMed PMC

Safferthal C, Rohde K, Fulda S. Therapeutic targeting of necroptosis by Smac mimetic bypasses apoptosis resistance in acute myeloid leukemia cells. Oncogene. 2017;36:1487–1502. doi: 10.1038/onc.2016.310. PubMed DOI

Mahoney DJ, et al. Both cIAP1 and cIAP2 regulate TNFalpha-mediated NF-kappaB activation. Proc. Natl Acad. Sci. USA. 2008;105:11778–11783. doi: 10.1073/pnas.0711122105. PubMed DOI PMC

Taraborrelli L, et al. LUBAC prevents lethal dermatitis by inhibiting cell death induced by TNF, TRAIL and CD95L. Nat. Commun. 2018;9:3910. doi: 10.1038/s41467-018-06155-8. PubMed DOI PMC

Amin P, et al. Regulation of a distinct activated RIPK1 intermediate bridging complex I and complex II in TNFα-mediated apoptosis. Proc. Natl Acad. Sci. USA. 2018;115:E5944–E5953. doi: 10.1073/pnas.1806973115. PubMed DOI PMC

Ruiz EJ, et al. LUBAC determines chemotherapy resistance in squamous cell lung cancer. J. Exp. Med. 2019;216:450–465. doi: 10.1084/jem.20180742. PubMed DOI PMC

Lun M, et al. Nuclear factor-kappaB pathway as a therapeutic target in head and neck squamous cell carcinoma: pharmaceutical and molecular validation in human cell lines using Velcade and siRNA/NF-kappaB. Ann. Clin. Lab Sci. 2005;35:251–258. PubMed

Duarte VM, et al. Curcumin enhances the effect of cisplatin in suppression of head and neck squamous cell carcinoma via inhibition of IKKβ protein of the NFκB pathway. Mol. Cancer Ther. 2010;9:2665–2675. doi: 10.1158/1535-7163.MCT-10-0064. PubMed DOI PMC

Duffey DC, et al. Inhibition of transcription factor nuclear factor-kappaB by a mutant inhibitor-kappaBalpha attenuates resistance of human head and neck squamous cell carcinoma to TNF-alpha caspase-mediated cell death. Br. J. Cancer. 2000;83:1367–1374. doi: 10.1054/bjoc.2000.1423. PubMed DOI PMC

Lim J. et al. Autophagy regulates inflammatory programmed cell death via turnover of RHIM-domain proteins. Elife. 8, e44452 (2019). PubMed PMC

Wu W, Stork B. Regulating RIPK1: another way in which ULK1 contributes to survival. Autophagy. 2020;16:1544–1546. doi: 10.1080/15548627.2020.1783110. PubMed DOI PMC

Bray K, et al. Autophagy suppresses RIP kinase-dependent necrosis enabling survival to mTOR inhibition. PloS ONE. 2012;7:e41831–e41831. doi: 10.1371/journal.pone.0041831. PubMed DOI PMC

Wu W, et al. The autophagy-initiating kinase ULK1 controls RIPK1-mediated cell death. Cell Rep. 2020;31:107547. doi: 10.1016/j.celrep.2020.107547. PubMed DOI

Su H, Li F, Ranek MJ, Wei N, Wang X. COP9 signalosome regulates autophagosome maturation. Circulation. 2011;124:2117–2128. doi: 10.1161/CIRCULATIONAHA.111.048934. PubMed DOI PMC

Xiao P, et al. COP9 signalosome suppresses RIPK1-RIPK3–mediated cardiomyocyte necroptosis in mice. Circ. Heart Fail. 2020;13:e006996. doi: 10.1161/CIRCHEARTFAILURE.120.006996. PubMed DOI PMC

Lee M-H, Zhao R, Phan L, Yeung S-CJ. Roles of COP9 signalosome in cancer. Cell Cycle. 2011;10:3057–3066. doi: 10.4161/cc.10.18.17320. PubMed DOI PMC

Joshi A, et al. Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1. Cell Death Differ. 2016;23:216–230. doi: 10.1038/cdd.2015.88. PubMed DOI PMC

Goodall ML, et al. The autophagy machinery controls cell death switching between apoptosis and necroptosis. Dev. Cell. 2016;37:337–349. doi: 10.1016/j.devcel.2016.04.018. PubMed DOI PMC

Yonekawa T. et al. RIP1 negatively regulates basal autophagic flux through TFEB to control sensitivity to apoptosis. EMBO Rep. 16, 700–708 (2015). PubMed PMC

Shlomovitz I, et al. Necroptosis directly induces the release of full-length biologically active IL-33 in vitro and in an inflammatory disease model. FEBS J. 2019;286:507–522. doi: 10.1111/febs.14738. PubMed DOI

Pastille E, et al. The IL-33/ST2 pathway shapes the regulatory T cell phenotype to promote intestinal cancer. Mucosal Immunol. 2019;12:990–1003. doi: 10.1038/s41385-019-0176-y. PubMed DOI PMC

Schiering C, et al. The alarmin IL-33 promotes regulatory T-cell function in the intestine. Nature. 2014;513:564–568. doi: 10.1038/nature13577. PubMed DOI PMC

Chen SF, et al. The paracrine effect of cancer-associated fibroblast-induced interleukin-33 regulates the invasiveness of head and neck squamous cell carcinoma. J. Pathol. 2013;231:180–189. doi: 10.1002/path.4226. PubMed DOI

Ishikawa K, et al. Expression of interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue. Auris Nasus Larynx. 2014;41:552–557. doi: 10.1016/j.anl.2014.08.007. PubMed DOI

Seifert L. et al. The necrosome promotes pancreatic oncogenesis via CXCL1 and Mincle-induced immune suppression. Nature. 2016;532:245–249. doi: 10.1038/nature17403. PubMed DOI PMC

Yatim N. et al. RIPK1 and NF-κB signaling in dying cells determines cross-priming of CD8+ T cells. Science. 2015;350:328–334. doi: 10.1126/science.aad0395. PubMed DOI PMC

Werthmöller N, Frey B, Wunderlich R, Fietkau R, Gaipl US. Modulation of radiochemoimmunotherapy-induced B16 melanoma cell death by the pan-caspase inhibitor zVAD-fmk induces anti-tumor immunity in a HMGB1-, nucleotide- and T-cell-dependent manner. Cell Death Dis. 2015;6:e1761. doi: 10.1038/cddis.2015.129. PubMed DOI PMC

Lu H, et al. Molecular targeted therapies elicit concurrent apoptotic and GSDME-dependent pyroptotic tumor cell death. Clin. Cancer Res. 2018;24:6066–6077. doi: 10.1158/1078-0432.CCR-18-1478. PubMed DOI

Wang Y, et al. Chemotherapy drugs induce pyroptosis through caspase-3 cleavage of a gasdermin. Nature. 2017;547:99–103. doi: 10.1038/nature22393. PubMed DOI

Sarhan J, et al. Caspase-8 induces cleavage of gasdermin D to elicit pyroptosis during Yersinia infection. Proc. Natl Acad. Sci. USA. 2018;115:E10888–E10897. doi: 10.1073/pnas.1809548115. PubMed DOI PMC

Chung CH, et al. Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression. Cancer Cell. 2004;5:489–500. doi: 10.1016/S1535-6108(04)00112-6. PubMed DOI

Taabazuing CY, Okondo MC, Bachovchin DA. Pyroptosis and apoptosis pathways engage in bidirectional crosstalk in monocytes and macrophages. Cell Chem. Biol. 2017;24:507–14.e4. doi: 10.1016/j.chembiol.2017.03.009. PubMed DOI PMC

Willson J. A matter of life and death for caspase 8. Nat. Rev. Mol. Cell Biol. 2020;21:63. doi: 10.1038/s41580-019-0201-8. PubMed DOI

Sun Q, et al. Caspase 1 activation is protective against hepatocyte cell death by up-regulating beclin 1 protein and mitochondrial autophagy in the setting of redox stress. J. Biol. Chem. 2013;288:15947–15958. doi: 10.1074/jbc.M112.426791. PubMed DOI PMC

Shi C-S, et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat. Immunol. 2012;13:255–263. doi: 10.1038/ni.2215. PubMed DOI PMC

Yuk J-M, Silwal P, Jo E-K. Inflammasome and mitophagy connection in health and disease. Int. J. Mol. Sci. 2020;21:4714. doi: 10.3390/ijms21134714. PubMed DOI PMC

Chen L, et al. Blockage of the NLRP3 inflammasome by MCC950 improves anti-tumor immune responses in head and neck squamous cell carcinoma. Cell Mol. Life Sci. 2018;75:2045–2058. doi: 10.1007/s00018-017-2720-9. PubMed DOI PMC

Wang H, et al. NLRP3 promotes tumor growth and metastasis in human oral squamous cell carcinoma. BMC Cancer. 2018;18:500. doi: 10.1186/s12885-018-4403-9. PubMed DOI PMC

Bae JY, et al. P2X7 receptor and NLRP3 inflammasome activation in head and neck cancer. Oncotarget. 2017;8:48972–48982. doi: 10.18632/oncotarget.16903. PubMed DOI PMC

Huang CF, et al. NLRP3 inflammasome activation promotes inflammation-induced carcinogenesis in head and neck squamous cell carcinoma. J. Exp. Clin. Cancer Res. 2017;36:116. doi: 10.1186/s13046-017-0589-y. PubMed DOI PMC

Feng X, et al. The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma. J. Exp. Clin. Cancer Res. 2017;36:81. doi: 10.1186/s13046-017-0553-x. PubMed DOI PMC

Stanam A, Gibson-Corley KN, Love-Homan L, Ihejirika N, Simons AL. Interleukin-1 blockade overcomes erlotinib resistance in head and neck squamous cell carcinoma. Oncotarget. 2016;7:76087–76100. doi: 10.18632/oncotarget.12590. PubMed DOI PMC

Wang F, et al. Alcohol accumulation promotes esophagitis via pyroptosis activation. Int. J. Biol. Sci. 2018;14:1245–1255. doi: 10.7150/ijbs.24347. PubMed DOI PMC

Ainouze M, et al. Human papillomavirus type 16 antagonizes IRF6 regulation of IL-1β. PLoS Pathog. 2018;14:e1007158. doi: 10.1371/journal.ppat.1007158. PubMed DOI PMC

So D, et al. Cervical cancer is addicted to SIRT1 disarming the AIM2 antiviral defense. Oncogene. 2018;37:5191–5204. doi: 10.1038/s41388-018-0339-4. PubMed DOI

Noguchi A, et al. SIRT1 expression is associated with good prognosis for head and neck squamous cell carcinoma patients. Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. 2013;115:385–392. doi: 10.1016/j.oooo.2012.12.013. PubMed DOI

Di Vincenzo S, et al. Cigarette smoke impairs Sirt1 activity and promotes pro-inflammatory responses in bronchial epithelial cells. Eur. Respir. J. 2015;46:PA5105.

Song Y, et al. HPV E7 inhibits cell pyroptosis by promoting TRIM21-mediated degradation and ubiquitination of the IFI16 inflammasome. Int. J. Biol. Sci. 2020;16:2924–2937. doi: 10.7150/ijbs.50074. PubMed DOI PMC

Rogers C, et al. Cleavage of DFNA5 by caspase-3 during apoptosis mediates progression to secondary necrotic/pyroptotic cell death. Nat. Commun. 2017;8:14128. doi: 10.1038/ncomms14128. PubMed DOI PMC

Segovia M. et al. Targeting TMEM176B enhances antitumor immunity and augments the efficacy of immune checkpoint blockers by unleashing inflammasome activation. Cancer Cell. 35, 767–781.e6 (2019). PubMed PMC

Zhang Z, et al. Gasdermin E suppresses tumour growth by activating anti-tumour immunity. Nature. 2020;579:415–420. doi: 10.1038/s41586-020-2071-9. PubMed DOI PMC

Rogers C, et al. Gasdermin pores permeabilize mitochondria to augment caspase-3 activation during apoptosis and inflammasome activation. Nat. Commun. 2019;10:1689. doi: 10.1038/s41467-019-09397-2. PubMed DOI PMC

Huang W. et al. DFNA5 attenuated in head and neck squamous cell carcinoma acquired with radio-resistance and associated with PD-L2 (2020).

Shan L, et al. Visualizing head and neck tumors in vivo using near-infrared fluorescent transferrin conjugate. Mol. Imaging. 2008;7:42–49. doi: 10.2310/7290.2008.0006. PubMed DOI

Lenarduzzi M, et al. Hemochromatosis enhances tumor progression via upregulation of intracellular iron in head and neck cancer. PloS ONE. 2013;8:e74075. doi: 10.1371/journal.pone.0074075. PubMed DOI PMC

Järvinen AK, et al. Identification of target genes in laryngeal squamous cell carcinoma by high-resolution copy number and gene expression microarray analyses. Oncogene. 2006;25:6997–7008. doi: 10.1038/sj.onc.1209690. PubMed DOI

Dixon SJ, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–1072. doi: 10.1016/j.cell.2012.03.042. PubMed DOI PMC

Jiang L, et al. Ferroptosis as a p53-mediated activity during tumour suppression. Nature. 2015;520:57–62. doi: 10.1038/nature14344. PubMed DOI PMC

Viswanathan VS, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–457. doi: 10.1038/nature23007. PubMed DOI PMC

Dohadwala M, et al. The role of ZEB1 in the inflammation-induced promotion of EMT in HNSCC. Otolaryngol. Head Neck Surg. 2010;142:753–759. doi: 10.1016/j.otohns.2010.01.034. PubMed DOI

Wu J, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2–YAP signalling. Nature. 2019;572:402–406. doi: 10.1038/s41586-019-1426-6. PubMed DOI PMC

Jung YS, Kato I, Kim HR. A novel function of HPV16-E6/E7 in epithelial-mesenchymal transition. Biochem. Biophys. Res. Commun. 2013;435:339–344. doi: 10.1016/j.bbrc.2013.04.060. PubMed DOI

Yagoda N, et al. RAS-RAF-MEK-dependent oxidative cell death involving voltage-dependent anion channels. Nature. 2007;447:864–868. doi: 10.1038/nature05859. PubMed DOI PMC

Wu Z, et al. Chaperone-mediated autophagy is involved in the execution of ferroptosis. Proc. Natl Acad. Sci. USA. 2019;116:2996–3005. doi: 10.1073/pnas.1819728116. PubMed DOI PMC

Gao M, et al. Ferroptosis is an autophagic cell death process. Cell Res. 2016;26:1021–1032. doi: 10.1038/cr.2016.95. PubMed DOI PMC

Belleudi F, Nanni M, Raffa S, Torrisi MR. HPV16 E5 deregulates the autophagic process in human keratinocytes. Oncotarget. 2015;6:9370–9386. doi: 10.18632/oncotarget.3326. PubMed DOI PMC

Mattoscio D., Medda A. & Chiocca S. Human papilloma virus and autophagy. Int. J. Mol. Sci. 19, 1775 (2018). PubMed PMC

Tingting C, et al. Human papillomavirus 16E6/E7 activates autophagy via Atg9B and LAMP1 in cervical cancer cells. Cancer Med. 2019;8:4404–4416. doi: 10.1002/cam4.2351. PubMed DOI PMC

Sewell A, et al. Reverse-phase protein array profiling of oropharyngeal cancer and significance of PIK3CA mutations in HPV-associated head and neck cancer. Clin. Cancer Res. 2014;20:2300–2311. doi: 10.1158/1078-0432.CCR-13-2585. PubMed DOI PMC

Pietrocola F, et al. Aspirin recapitulates features of caloric restriction. Cell Rep. 2018;22:2395–2407. doi: 10.1016/j.celrep.2018.02.024. PubMed DOI PMC

Castoldi F, Pietrocola F, Maiuri MC, Kroemer G. Aspirin induces autophagy via inhibition of the acetyltransferase EP300. Oncotarget. 2018;9:24574–24575. doi: 10.18632/oncotarget.25364. PubMed DOI PMC

Hedberg ML, et al. Use of nonsteroidal anti-inflammatory drugs predicts improved patient survival for PIK3CA-altered head and neck cancer. J. Exp. Med. 2019;216:419–427. doi: 10.1084/jem.20181936. PubMed DOI PMC

Wu SY, et al. Ionizing radiation induces autophagy in human oral squamous cell carcinoma. J. BUON. 2014;19:137–144. PubMed

Kamarajan P, et al. Head and neck squamous cell carcinoma metabolism draws on glutaminolysis, and stemness is specifically regulated by glutaminolysis via aldehyde dehydrogenase. J. Proteome Res. 2017;16:1315–1326. doi: 10.1021/acs.jproteome.6b00936. PubMed DOI PMC

Gao M, Jiang X. To eat or not to eat—the metabolic flavor of ferroptosis. Curr. Opin. Cell Biol. 2018;51:58–64. doi: 10.1016/j.ceb.2017.11.001. PubMed DOI PMC

Yang J, et al. Targeting cellular metabolism to reduce head and neck cancer growth. Sci. Rep. 2019;9:4995. doi: 10.1038/s41598-019-41523-4. PubMed DOI PMC

Okazaki S, et al. Glutaminolysis-related genes determine sensitivity to xCT-targeted therapy in head and neck squamous cell carcinoma. Cancer Sci. 2019;110:3453–3463. doi: 10.1111/cas.14182. PubMed DOI PMC

Zhang Z, et al. ASCT2 (SLC1A5)-dependent glutamine uptake is involved in the progression of head and neck squamous cell carcinoma. Br. J. Cancer. 2020;122:82–93. doi: 10.1038/s41416-019-0637-9. PubMed DOI PMC

Zimmermann P, Bette M, Giel G, Stuck BA, Mandic R. Influence of the xc-cystine/glutamate antiporter inhibitor sulfasalazine on the growth of head and neck squamous cell carcinoma cell lines. Laryngo Rhino Otol. 2018;97:10050.

Okazaki S, et al. Synthetic lethality of the ALDH3A1 inhibitor dyclonine and xCT inhibitors in glutathione deficiency-resistant cancer cells. Oncotarget. 2018;9:33832–33843. doi: 10.18632/oncotarget.26112. PubMed DOI PMC

Tao X, et al. AP1G1 is involved in cetuximab-mediated downregulation of ASCT2-EGFR complex and sensitization of human head and neck squamous cell carcinoma cells to ROS-induced apoptosis. Cancer Lett. 2017;408:33–42. doi: 10.1016/j.canlet.2017.08.012. PubMed DOI PMC

Yoshikawa M, et al. xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res. 2013;73:1855–1866. doi: 10.1158/0008-5472.CAN-12-3609-T. PubMed DOI

Zhang P, et al. xCT expression modulates cisplatin resistance in Tca8113 tongue carcinoma cells. Oncol. Lett. 2016;12:307–314. doi: 10.3892/ol.2016.4571. PubMed DOI PMC

Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol. Cell. 2015;59:298–308. doi: 10.1016/j.molcel.2015.06.011. PubMed DOI PMC

Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT. Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron. 1989;2:1547–1558. doi: 10.1016/0896-6273(89)90043-3. PubMed DOI

Yang L, et al. Targeting stromal glutamine synthetase in tumors disrupts tumor microenvironment-regulated cancer cell growth. Cell Metab. 2016;24:685–700. doi: 10.1016/j.cmet.2016.10.011. PubMed DOI PMC

Ferber MJ, et al. Preferential integration of human papillomavirus type 18 near the c-myc locus in cervical carcinoma. Oncogene. 2003;22:7233–7242. doi: 10.1038/sj.onc.1207006. PubMed DOI

Liu L, et al. Identification of reliable biomarkers of human papillomavirus 16 methylation in cervical lesions based on integration status using high-resolution melting analysis. Clin. Epigenetics. 2018;10:10. doi: 10.1186/s13148-018-0445-8. PubMed DOI PMC

Palmieri EM, et al. Pharmacologic or genetic targeting of glutamine synthetase skews macrophages toward an M1-like phenotype and inhibits tumor metastasis. Cell Rep. 2017;20:1654–1666. doi: 10.1016/j.celrep.2017.07.054. PubMed DOI PMC

Fazzari J, Linher-Melville K, Singh G. Tumour-derived glutamate: linking aberrant cancer cell metabolism to peripheral sensory pain pathways. Curr. Neuropharmacol. 2017;15:620–636. doi: 10.2174/1570159X14666160509123042. PubMed DOI PMC

Bertero T, et al. Tumor-stroma mechanics coordinate amino acid availability to sustain tumor growth and malignancy. Cell Metab. 2019;29:124–40.e10. doi: 10.1016/j.cmet.2018.09.012. PubMed DOI PMC

Wang Y, et al. Fibroblasts in head and neck squamous cell carcinoma associated with perineural invasion have high-level nuclear yes-associated protein (YAP) expression. Acad. Pathol. 2015;2:2374289515616972. doi: 10.1177/2374289515616972. PubMed DOI PMC

Ge L, et al. Yes-associated protein expression in head and neck squamous cell carcinoma nodal metastasis. PloS ONE. 2011;6:e27529. doi: 10.1371/journal.pone.0027529. PubMed DOI PMC

García-Escudero R, et al. Overexpression of PIK3CA in head and neck squamous cell carcinoma is associated with poor outcome and activation of the YAP pathway. Oral. Oncol. 2018;79:55–63. doi: 10.1016/j.oraloncology.2018.02.014. PubMed DOI

LeBlanc L. et al. Yap1 safeguards mouse embryonic stem cells from excessive apoptosis during differentiation. Elife. 7, e40167 (2018) PubMed PMC

Wang W, et al. CD8(+) T cells regulate tumour ferroptosis during cancer immunotherapy. Nature. 2019;569:270–274. doi: 10.1038/s41586-019-1170-y. PubMed DOI PMC

Yamazaki T, et al. Defective immunogenic cell death of HMGB1-deficient tumors: compensatory therapy with TLR4 agonists. Cell Death Differ. 2014;21:69–78. doi: 10.1038/cdd.2013.72. PubMed DOI PMC

Wen Q, Liu J, Kang R, Zhou B, Tang D. The release and activity of HMGB1 in ferroptosis. Biochem. Biophys. Res. Commun. 2019;510:278–283. doi: 10.1016/j.bbrc.2019.01.090. PubMed DOI

Wild CA, et al. HMGB1 is overexpressed in tumor cells and promotes activity of regulatory T cells in patients with head and neck cancer. Oral. Oncol. 2012;48:409–416. doi: 10.1016/j.oraloncology.2011.12.009. PubMed DOI

Yang WS, et al. Regulation of ferroptotic cancer cell death by GPX4. Cell. 2014;156:317–331. doi: 10.1016/j.cell.2013.12.010. PubMed DOI PMC

Kim EH, Shin D, Lee J, Jung AR, Roh J-L. CISD2 inhibition overcomes resistance to sulfasalazine-induced ferroptotic cell death in head and neck cancer. Cancer Lett. 2018;432:180–190. doi: 10.1016/j.canlet.2018.06.018. PubMed DOI

Roh JL, Kim EH, Jang HJ, Park JY, Shin D. Induction of ferroptotic cell death for overcoming cisplatin resistance of head and neck cancer. Cancer Lett. 2016;381:96–103. doi: 10.1016/j.canlet.2016.07.035. PubMed DOI

Lang X, et al. Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Disco. 2019;9:1673–1685. doi: 10.1158/2159-8290.CD-19-0338. PubMed DOI PMC

Lin R, et al. Dihydroartemisinin (DHA) induces ferroptosis and causes cell cycle arrest in head and neck carcinoma cells. Cancer Lett. 2016;381:165–175. doi: 10.1016/j.canlet.2016.07.033. PubMed DOI

Shaw AT, et al. Selective killing of K-ras mutant cancer cells by small molecule inducers of oxidative stress. Proc. Natl Acad. Sci. USA. 2011;108:8773–8778. doi: 10.1073/pnas.1105941108. PubMed DOI PMC

Chen JJ, Galluzzi L. Fighting resilient cancers with iron. Trends Cell Biol. 2018;28:77–78. doi: 10.1016/j.tcb.2017.11.007. PubMed DOI

Pisanti S, Picardi P, Ciaglia E, D’Alessandro A, Bifulco M. Novel prospects of statins as therapeutic agents in cancer. Pharm. Res. 2014;88:84–98. doi: 10.1016/j.phrs.2014.06.013. PubMed DOI

Cruz SA, Qin Z, Stewart AFR, Chen HH. Dabrafenib, an inhibitor of RIP3 kinase-dependent necroptosis, reduces ischemic brain injury. Neural Regen. Res. 2018;13:252–256. doi: 10.4103/1673-5374.226394. PubMed DOI PMC

Fulda S. Repurposing anticancer drugs for targeting necroptosis. Cell Cycle. 2018;17:829–832. doi: 10.1080/15384101.2018.1442626. PubMed DOI PMC

Yang H, et al. Contribution of RIP3 and MLKL to immunogenic cell death signaling in cancer chemotherapy. Oncoimmunology. 2016;5:e1149673–e1149673. doi: 10.1080/2162402X.2016.1149673. PubMed DOI PMC

Oliver Metzig M, et al. Inhibition of caspases primes colon cancer cells for 5-fluorouracil-induced TNF-α-dependent necroptosis driven by RIP1 kinase and NF-κB. Oncogene. 2016;35:3399–3409. doi: 10.1038/onc.2015.398. PubMed DOI

Huang X, et al. Bypassing drug resistance by triggering necroptosis: recent advances in mechanisms and its therapeutic exploitation in leukemia. J. Exp. Clin. Cancer Res. 2018;37:310. doi: 10.1186/s13046-018-0976-z. PubMed DOI PMC

Valter K, Zhivotovsky B, Gogvadze V. Cell death-based treatment of neuroblastoma. Cell Death Dis. 2018;9:113. doi: 10.1038/s41419-017-0060-1. PubMed DOI PMC

Zhang CC, et al. Chemotherapeutic paclitaxel and cisplatin differentially induce pyroptosis in A549 lung cancer cells via caspase-3/GSDME activation. Apoptosis. 2019;24:312–325. doi: 10.1007/s10495-019-01515-1. PubMed DOI

Johnson DC, et al. DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat. Med. 2018;24:1151–1156. doi: 10.1038/s41591-018-0082-y. PubMed DOI PMC

Woo JH, et al. Elucidating compound mechanism of action by network perturbation analysis. Cell. 2015;162:441–451. doi: 10.1016/j.cell.2015.05.056. PubMed DOI PMC

Lachaier E, et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res. 2014;34:6417–6422. PubMed

Möckelmann N, et al. Effect of sorafenib on cisplatin-based chemoradiation in head and neck cancer cells. Oncotarget. 2016;7:23542–23551. doi: 10.18632/oncotarget.8275. PubMed DOI PMC

Guo J, et al. Ferroptosis: a novel anti-tumor action for Cisplatin. Cancer Res. Treat. 2018;50:445–460. doi: 10.4143/crt.2016.572. PubMed DOI PMC

Liu T., Zhang J., Li K., Deng L. & Wang H. Combination of an autophagy inducer and an autophagy inhibitor: a smarter strategy emerging in cancer therapy. Front. Pharmacol. 11, 408 (2020). PubMed PMC

Chude C. I. & Amaravadi R. K. Targeting autophagy in cancer: update on clinical trials and novel inhibitors. Int. J. Mol. Sci. 18, 1279 (2017). PubMed PMC

Al-Bari MA. Chloroquine analogues in drug discovery: new directions of uses, mechanisms of actions and toxic manifestations from malaria to multifarious diseases. J. Antimicrob. Chemother. 2015;70:1608–1621. doi: 10.1093/jac/dkv018. PubMed DOI PMC

Maiuri MC, et al. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L) Autophagy. 2007;3:374–376. doi: 10.4161/auto.4237. PubMed DOI

Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol. Biomark. Prev. 2005;14:467–475. doi: 10.1158/1055-9965.EPI-04-0551. PubMed DOI

Descamps G, Wattiez R, Saussez S. Proteomic study of HPV-positive head and neck cancers: preliminary results. BioMed. Res. Int. 2014;2014:430906. doi: 10.1155/2014/430906. PubMed DOI PMC

Canning M, et al. Heterogeneity of the head and neck squamous cell carcinoma immune landscape and its impact on immunotherapy. Front. Cell Dev. Biol. 2019;7:52. doi: 10.3389/fcell.2019.00052. PubMed DOI PMC

Kobayashi K, et al. A review of HPV-related head and neck cancer. J. Clin. Med. 2018;7:241. doi: 10.3390/jcm7090241. PubMed DOI PMC