Clin Exp Otorhinolaryngol.  2025 Aug;18(3):210-224. 10.21053/ceo.2025-00029.

Radioresistance Mechanisms in Head and Neck Cancer

• Nguyen QK
• Koo BS

• KMID: 2571249
• DOI: http://doi.org/10.21053/ceo.2025-00029

Abstract

Head and neck cancer (HNC) is not only one of the deadliest malignant tumors but also significantly impacts patient quality of life because of its proximity to numerous critical organs. Radiotherapy is commonly used to treat HNC due to its effectiveness in targeting cancer cells while sparing adjacent organs. However, the emergence of radioresistance severely limits the efficacy of radiotherapy, frequently leading to poor prognosis and treatment failure. Consequently, an enhanced understanding of the underlying mechanisms of radioresistance could facilitate the development of novel treatment strategies aimed at reducing recurrence rates and improving survival outcomes. In this review, we summarize the primary mechanisms implicated in radioresistance in HNC from both cancer cell-intrinsic and tumor microenvironment perspectives. Furthermore, we discuss currently available radiation-sensitizing approaches to overcome radioresistance in HNC.

Keyword

Head and Neck Cancer; Radiotherapy; Radiation Resistance; Neoplastic Cells; Tumor Microenvironment

Reference

1. National Cancer Institute. Head and neck cancers [Internet]. National Cancer Institute; 2021 [cited 2025 Apr 20]. Available from: https://www.cancer.gov/types/head-and-neck/head-neck-fact-sheet.

2. El-Naggar AK, Chan JK, Grandis JR, Takata T, Slootweg PJ. WHO classification of head and neck tumours. World Health Organization; 2017.

3. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021; May. 71(3):209–49.

4. Patterson RH, Fischman VG, Wasserman I, Siu J, Shrime MG, Fagan JJ, et al. Global burden of head and neck cancer: economic consequences, health, and the role of surgery. Otolaryngol Head Neck Surg. 2020; Mar. 162(3):296–303.

5. Sharma Y, Mishra G, Parikh V. Quality of life in head and neck cancer patients. Indian J Otolaryngol Head Neck Surg. 2019; Oct. 71(Suppl 1):927–32.

6. Harreus U. Surgical errors and risks: the head and neck cancer patient. GMS Curr Top Otorhinolaryngol Head Neck Surg. 2013; Dec. 12:Doc04.

7. Martin AM, Elliott ZT, Chisolm P, Crossley J, Maxwell JH, Pierce M, et al. Perioperative complications among head and neck surgery patients with COVID-19. Head Neck. 2023; Dec. 45(12):3033–41.

8. Haimovitz-Friedman A, Kolesnick RN, Fuks Z. Modulation of the apoptotic response: potential for improving the outcome in clinical radiotherapy. Semin Radiat Oncol. 1996; Oct. 6(4):273–83.

9. De Crevoisier R, Domenge C, Wibault P, Koscielny S, Lusinchi A, Janot F, et al. Full dose reirradiation combined with chemotherapy after salvage surgery in head and neck carcinoma. Cancer. 2001; Jun. 91(11):2071–6.

10. Pollard C, Nguyen TP, Ng SP, Frank SJ, Garden AS, Gunn GB, et al. Clinical outcomes after local field conformal reirradiation of patients with retropharyngeal nodal metastasis. Head Neck. 2017; Oct. 39(10):2079–87.

11. Kim YS. Reirradiation of head and neck cancer in the era of intensity-modulated radiotherapy: patient selection, practical aspects, and current evidence. Radiat Oncol J. 2017; Mar. 35(1):1–15.

12. Lee J, Shin IS, Kim WC, Yoon WS, Koom WS, Rim CH. Reirradiation with intensity-modulated radiation therapy for recurrent or secondary head and neck cancer: meta-analysis and systematic review. Head Neck. 2020; Sep. 42(9):2473–85.

13. Lee J, Kim WC, Yoon WS, Koom WS, Rim CH. Reirradiation using stereotactic body radiotherapy in the management of recurrent or second primary head and neck cancer: a meta-analysis and systematic review. Oral Oncol. 2020; Aug. 107:104757.

14. Steel GG, McMillan TJ, Peacock JH. The 5Rs of radiobiology. Int J Radiat Biol. 1989; Dec. 56(6):1045–8.

15. Hubenak JR, Zhang Q, Branch CD, Kronowitz SJ. Mechanisms of injury to normal tissue after radiotherapy: a review. Plast Reconstr Surg. 2014; Jan. 133(1):49e–56e.

16. Pajonk F, Vlashi E, McBride WH. Radiation resistance of cancer stem cells: the 4 R’s of radiobiology revisited. Stem Cells. 2010; Apr. 28(4):639–48.

17. Lindahl T, Barnes DE. Repair of endogenous DNA damage. Cold Spring Harb Symp Quant Biol. 2000; 65:127–33.

18. Vignard J, Mirey G, Salles B. Ionizing-radiation induced DNA double-strand breaks: a direct and indirect lighting up. Radiother Oncol. 2013; Sep. 108(3):362–9.

19. Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009; Oct. 461(7267):1071–8.

20. Lane D, Levine A. p53 Research: the past thirty years and the next thirty years. Cold Spring Harb Perspect Biol. 2010; Dec. 2(12):a000893.

21. Engeland K. Cell cycle regulation: p53-p21-RB signaling. Cell Death Differ. 2022; May. 29(5):946–60.

22. Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X, et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 2022; Nov. 13(11):974.

23. Li GM. Mechanisms and functions of DNA mismatch repair. Cell Res. 2008; Jan. 18(1):85–98.

24. Kumar N, Moreno NC, Feltes BC, Menck CF, Houten BV. Cooperation and interplay between base and nucleotide excision repair pathways: from DNA lesions to proteins. Genet Mol Biol. 2020; Mar. 43(1 suppl. 1):e20190104.

25. Eustermann S, Wu WF, Langelier MF, Yang JC, Easton LE, Riccio AA, et al. Structural basis of detection and signaling of DNA single-strand breaks by human PARP-1. Mol Cell. 2015; Dec. 60(5):742–54.

26. Langelier MF, Riccio AA, Pascal JM. PARP-2 and PARP-3 are selectively activated by 5’ phosphorylated DNA breaks through an allosteric regulatory mechanism shared with PARP-1. Nucleic Acids Res. 2014; Jul. 42(12):7762–75.

27. Pardo B, Gomez-Gonzalez B, Aguilera A. DNA repair in mammalian cells: DNA double-strand break repair: how to fix a broken relationship. Cell Mol Life Sci. 2009; Mar. 66(6):1039–56.

28. Shibata A, Conrad S, Birraux J, Geuting V, Barton O, Ismail A, et al. Factors determining DNA double-strand break repair pathway choice in G2 phase. EMBO J. 2011; Mar. 30(6):1079–92.

29. Paques F, Haber JE. Multiple pathways of recombination induced by double-strand breaks in Saccharomyces cerevisiae. Microbiol Mol Biol Rev. 1999; Jun. 63(2):349–404.

30. Moynahan ME, Jasin M. Mitotic homologous recombination maintains genomic stability and suppresses tumorigenesis. Nat Rev Mol Cell Biol. 2010; Mar. 11(3):196–207.

31. Lieber MR. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway. Annu Rev Biochem. 2010; Jul. 79:181–211.

32. Polo SE, Jackson SP. Dynamics of DNA damage response proteins at DNA breaks: a focus on protein modifications. Genes Dev. 2011; Mar. 25(5):409–33.

33. Yue X, Bai C, Xie D, Ma T, Zhou PK. DNA-PKcs: a multi-faceted player in DNA damage response. Front Genet. 2020; Dec. 11:607428.

34. Jiang Y, Chu WK. Potential roles of the retinoblastoma protein in regulating genome editing. Front Cell Dev Biol. 2018; Jul. 6:81.

35. Psyrri A, Gkotzamanidou M, Papaxoinis G, Krikoni L, Economopoulou P, Kotsantis I, et al. The DNA damage response network in the treatment of head and neck squamous cell carcinoma. ESMO Open. 2021; Apr. 6(2):100075.

36. Weaver DT. What to do at an end: DNA double-strand-break repair. Trends Genet. 1995; Oct. 11(10):388–92.

37. Zou J, Qiao X, Ye H, Yang Y, Zheng X, Zhao H, et al. Antisense inhibition of ATM gene enhances the radiosensitivity of head and neck squamous cell carcinoma in mice. J Exp Clin Cancer Res. 2008; Oct. 27(1):56.

38. Guo Z, Wang YH, Xu H, Yuan CS, Zhou HH, Huang WH, et al. LncRNA linc00312 suppresses radiotherapy resistance by targeting DNA-PKcs and impairing DNA damage repair in nasopharyngeal carcinoma. Cell Death Dis. 2021; Jan. 12(1):69.

39. Banerjee R, Russo N, Liu M, Basrur V, Bellile E, Palanisamy N, et al. TRIP13 promotes error-prone nonhomologous end joining and induces chemoresistance in head and neck cancer. Nat Commun. 2014; Jul. 5:4527.

40. Zong WX, Thompson CB. Necrotic death as a cell fate. Genes Dev. 2006; Jan. 20(1):1–15.

41. Vaupel P, Schlenger K, Knoop C, Hockel M. Oxygenation of human tumors: evaluation of tissue oxygen distribution in breast cancers by computerized O2 tension measurements. Cancer Res. 1991; Jun. 51(12):3316–22.

42. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol. 1953; Dec. 26(312):638–48.

43. Yamamoto A, Huang Y, Krajina BA, McBirney M, Doak AE, Qu S, et al. Metastasis from the tumor interior and necrotic core formation are regulated by breast cancer-derived angiopoietin-like 7. Proc Natl Acad Sci U S A. 2023; Mar. 120(10):e2214888120.

44. Nossing C, Ryan KM. 50 years on and still very much alive: ‘Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics’. Br J Cancer. 2023; Feb. 128(3):426–31.

45. Moldoveanu T, Czabotar PE. BAX, BAK, and BOK: a coming of age for the BCL-2 family effector proteins. Cold Spring Harb Perspect Biol. 2020; Apr. 12(4):a036319.

46. Widden H, Placzek WJ. The multiple mechanisms of MCL1 in the regulation of cell fate. Commun Biol. 2021; Sep. 4(1):1029.

47. Replogle JM, Zhou W, Amaro AE, McFarland JM, Villalobos-Ortiz M, Ryan J, et al. Aneuploidy increases resistance to chemotherapeutics by antagonizing cell division. Proc Natl Acad Sci U S A. 2020; Dec. 117(48):30566–76.

48. Collins NL, Reginato MJ, Paulus JK, Sgroi DC, Labaer J, Brugge JS. G1/S cell cycle arrest provides anoikis resistance through Erk-mediated Bim suppression. Mol Cell Biol. 2005; Jun. 25(12):5282–91.

49. Yoshiba S, Ito D, Nagumo T, Shirota T, Hatori M, Shintani S. Hypoxia induces resistance to 5-fluorouracil in oral cancer cells via G(1) phase cell cycle arrest. Oral Oncol. 2009; Feb. 45(2):109–15.

50. Faried A, Sohda M, Nakajima M, Miyazaki T, Kato H, Kuwano H. Expression of heat-shock protein Hsp60 correlated with the apoptotic index and patient prognosis in human oesophageal squamous cell carcinoma. Eur J Cancer. 2004; Dec. 40(18):2804–11.

51. Lee JH, Sun D, Cho KJ, Kim MS, Hong MH, Kim IK, et al. Overexpression of human 27 kDa heat shock protein in laryngeal cancer cells confers chemoresistance associated with cell growth delay. J Cancer Res Clin Oncol. 2007; Jan. 133(1):37–46.

52. Ma R, Zhao LN, Yang H, Wang YF, Hu J, Zang J, et al. RNA binding motif protein 3 (RBM3) drives radioresistance in nasopharyngeal carcinoma by reducing apoptosis via the PI3K/AKT/Bcl-2 signaling pathway. Am J Transl Res. 2018; Dec. 10(12):4130–40.

53. Condon LT, Ashman JN, Ell SR, Stafford ND, Greenman J, Cawkwell L. Overexpression of Bcl-2 in squamous cell carcinoma of the larynx: a marker of radioresistance. Int J Cancer. 2002; Aug. 100(4):472–5.

54. Abuetabh Y, Wu HH, Chai C, Al Yousef H, Persad S, Sergi CM, et al. DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities. Exp Mol Med. 2022; Oct. 54(10):1658–69.

55. Zuckerman V, Wolyniec K, Sionov RV, Haupt S, Haupt Y. Tumour suppression by p53: the importance of apoptosis and cellular senescence. J Pathol. 2009; Sep. 219(1):3–15.

56. Wang JC, Baddock HT, Mafi A, Foe IT, Bratkowski M, Lin TY, et al. Structure of the p53 degradation complex from HPV16. Nat Commun. 2024; Feb. 15(1):1842.

57. Mirestean CC, Iancu RI, Iancu DP. p53 modulates radiosensitivity in head and neck cancers-from classic to future horizons. Diagnostics (Basel). 2022; Dec. 12(12):3052.

58. Gottgens EL, Ostheimer C, Span PN, Bussink J, Hammond EM. HPV, hypoxia and radiation response in head and neck cancer. Br J Radiol. 2019; Jan. 92(1093):20180047.

59. Hong A, Zhang X, Jones D, Veillard AS, Zhang M, Martin A, et al. Relationships between p53 mutation, HPV status and outcome in oropharyngeal squamous cell carcinoma. Radiother Oncol. 2016; Feb. 118(2):342–9.

60. Li X, Fang P, Mai J, Choi ET, Wang H, Yang XF. Targeting mitochondrial reactive oxygen species as novel therapy for inflammatory diseases and cancers. J Hematol Oncol. 2013; Feb. 6:19.

61. Auten RL, Davis JM. Oxygen toxicity and reactive oxygen species: the devil is in the details. Pediatr Res. 2009; Aug. 66(2):121–7.

62. Espinosa-Diez C, Miguel V, Mennerich D, Kietzmann T, Sanchez-Perez P, Cadenas S, et al. Antioxidant responses and cellular adjustments to oxidative stress. Redox Biol. 2015; Dec. 6:183–97.

63. Sun Z, Zhang S, Chan JY, Zhang DD. Keap1 controls postinduction repression of the Nrf2-mediated antioxidant response by escorting nuclear export of Nrf2. Mol Cell Biol. 2007; Sep. 27(18):6334–49.

64. Ma Q. Role of nrf2 in oxidative stress and toxicity. Annu Rev Pharmacol Toxicol. 2013; Jan. 53:401–26.

65. Guan L, Nambiar DK, Cao H, Viswanathan V, Kwok S, Hui AB, et al. NFE2L2 mutations enhance radioresistance in head and neck cancer by modulating intratumoral myeloid cells. Cancer Res. 2023; Mar. 83(6):861–74.

66. Sheth S, Farquhar DR, Schrank TP, Stepp W, Mazul A, Hayward M, et al. Correlation of alterations in the KEAP1/CUL3/NFE2L2 pathway with radiation failure in larynx squamous cell carcinoma. Laryngoscope Investig Otolaryngol. 2021; Jun. 6(4):699–707.

67. Warburg O. Uber den stoffwechsel der carcinomzelle. Naturwissenschaften. 1924; Dec. 12(50):1131–37.

68. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011; Mar. 144(5):646–74.

69. Kim SH, Baek KH. Regulation of cancer metabolism by deubiquitinating enzymes: the Warburg effect. Int J Mol Sci. 2021; Jun. 22(12):6173.

70. Yang Y, An Y, Ren M, Wang H, Bai J, Du W, et al. The mechanisms of action of mitochondrial targeting agents in cancer: inhibiting oxidative phosphorylation and inducing apoptosis. Front Pharmacol. 2023; Oct. 14:1243613.

71. Mirestean CC, Iancu RI, Iancu DP. New horizons in modulating the radio-sensitivity of head and neck cancer: 100 years after Warburg’ effect discovery. Front Oncol. 2022; Dec. 12:908695.

72. Takahashi H, Kawabata-Iwakawa R, Ida S, Mito I, Tada H, Chikamatsu K. Upregulated glycolysis correlates with tumor progression and immune evasion in head and neck squamous cell carcinoma. Sci Rep. 2021; Sep. 11(1):17789.

73. Courtnay R, Ngo DC, Malik N, Ververis K, Tortorella SM, Karagiannis TC. Cancer metabolism and the Warburg effect: the role of HIF-1 and PI3K. Mol Biol Rep. 2015; Apr. 42(4):841–51.

74. Toschi A, Lee E, Thompson S, Gadir N, Yellen P, Drain CM, et al. Phospholipase D-mTOR requirement for the Warburg effect in human cancer cells. Cancer Lett. 2010; Dec. 299(1):72–9.

75. Robey RB, Hay N. Is Akt the “Warburg kinase”?-Akt-energy metabolism interactions and oncogenesis. Semin Cancer Biol. 2009; Feb. 19(1):25–31.

76. Glorieux M, Dok R, Nuyts S. The influence of PI3K inhibition on the radiotherapy response of head and neck cancer cells. Sci Rep. 2020; Oct. 10(1):16208.

77. Zhang W, Li L, Guo E, Zhou H, Ming J, Sun L, et al. Inhibition of PDK1 enhances radiosensitivity and reverses epithelial-mesenchymal transition in nasopharyngeal carcinoma. Head Neck. 2022; Jul. 44(7):1576–87.

78. Mathew R, Karantza-Wadsworth V, White E. Role of autophagy in cancer. Nat Rev Cancer. 2007; Dec. 7(12):961–7.

79. Kim YC, Guan KL. mTOR: a pharmacologic target for autophagy regulation. J Clin Invest. 2015; Jan. 125(1):25–32.

80. Digomann D, Kurth I, Tyutyunnykova A, Chen O, Lock S, Gorodetska I, et al. The CD98 heavy chain is a marker and regulator of head and neck squamous cell carcinoma radiosensitivity. Clin Cancer Res. 2019; May. 25(10):3152–63.

81. Digomann D, Linge A, Dubrovska A. SLC3A2/CD98hc, autophagy and tumor radioresistance: a link confirmed. Autophagy. 2019; Oct. 15(10):1850–1.

82. Yu M, Qin K, Fan J, Zhao G, Zhao P, Zeng W, et al. The evolving roles of Wnt signaling in stem cell proliferation and differentiation, the development of human diseases, and therapeutic opportunities. Genes Dis. 2023; Jul. 11(3):101026.

83. Nager M, Sallan MC, Visa A, Pushparaj C, Santacana M, Macia A, et al. Inhibition of WNT-CTNNB1 signaling upregulates SQSTM1 and sensitizes glioblastoma cells to autophagy blockers. Autophagy. 2018; 14(4):619–36.

84. Ndoye A, Budina-Kolomets A, Kugel CH, Webster MR, Kaur A, Behera R, et al. ATG5 mediates a positive feedback loop between Wnt signaling and autophagy in melanoma. Cancer Res. 2017; Nov. 77(21):5873–85.

85. Lu Z, Zhou Y, Jing Q. Wnt5a-mediated autophagy promotes radiation resistance of nasopharyngeal carcinoma. J Cancer. 2022; Apr. 13(7):2388–96.

86. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016; Jan-Feb. 66(1):7–30.

87. Savagner P. The epithelial-mesenchymal transition (EMT) phenomenon. Ann Oncol. 2010; Oct. 21 Suppl 7:vii89–92.

88. Celia-Terrassa T, Kang Y. How important is EMT for cancer metastasis. PLoS Biol. 2024; Feb. 22(2):e3002487.

89. Steinbichler TB, Alshaimaa A, Maria MV, Daniel D, Herbert R, Jozsef D, et al. Epithelial-mesenchymal crosstalk induces radioresistance in HNSCC cells. Oncotarget. 2017; Dec. 9(3):3641–52.

90. Wang J, Chen Y, Xiang F, Li M, Li H, Chi J, et al. Suppression of TGF-β1 enhances chemosensitivity of cisplatin-resistant lung cancer cells through the inhibition of drug-resistant proteins. Artif Cells Nanomed Biotechnol. 2018; Nov. 46(7):1505–12.

91. Bao B, Ahmad A, Azmi AS, Ali S, Sarkar FH. Overview of cancer stem cells (CSCs) and mechanisms of their regulation: implications for cancer therapy. Curr Protoc Pharmacol. 2013; Jun. 61(1):14–25.

92. Bertrand G, Maalouf M, Boivin A, Battiston-Montagne P, Beuve M, Levy A, et al. Targeting head and neck cancer stem cells to overcome resistance to photon and carbon ion radiation. Stem Cell Rev Rep. 2014; Feb. 10(1):114–26.

93. Preca BT, Bajdak K, Mock K, Sundararajan V, Pfannstiel J, Maurer J, et al. A self-enforcing CD44s/ZEB1 feedback loop maintains EMT and stemness properties in cancer cells. Int J Cancer. 2015; Dec. 137(11):2566–77.

94. Bhola NE, Balko JM, Dugger TC, Kuba MG, Sanchez V, Sanders M, et al. TGF-β inhibition enhances chemotherapy action against triple-negative breast cancer. J Clin Invest. 2013; Mar. 123(3):1348–58.

95. Pal A, Barrett TF, Paolini R, Parikh A, Puram SV. Partial EMT in head and neck cancer biology: a spectrum instead of a switch. Oncogene. 2021; Aug. 40(32):5049–65.

96. Park YM, Lee SY, Park SW, Kim SH. Role of cancer stem cell in radioresistant head and neck cancer. Auris Nasus Larynx. 2016; Oct. 43(5):556–61.

97. Cho KJ, Park EJ, Kim MS, Joo YH. Characterization of FaDu-R, a radioresistant head and neck cancer cell line, and cancer stem cells. Auris Nasus Larynx. 2018; Jun. 45(3):566–73.

98. Maas AM, Abel LJ, Barnwell H, Bo A, Sudmeier LJ, Nickel KP, et al. Therapy resistance in head and neck cancer stem cells. Int J Radiat Oncol Biol Phys. 2018; Apr. 100(5):P1376.

99. Rodriguez-Meira A, Buck G, Clark SA, Povinelli BJ, Alcolea V, Louka E, et al. Unravelling intratumoral heterogeneity through high-sensitivity single-cell mutational analysis and parallel RNA sequencing. Mol Cell. 2019; Mar. 73(6):1292–305.e8.

100. Burrell RA, McGranahan N, Bartek J, Swanton C. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013; Sep. 501(7467):338–45.

101. Hao JJ, Lin DC, Dinh HQ, Mayakonda A, Jiang YY, Chang C, et al. Spatial intratumoral heterogeneity and temporal clonal evolution in esophageal squamous cell carcinoma. Nat Genet. 2016; Dec. 48(12):1500–7.

102. Harbst K, Lauss M, Cirenajwis H, Isaksson K, Rosengren F, Torngren T, et al. Multiregion whole-exome sequencing uncovers the genetic evolution and mutational heterogeneity of early-stage metastatic melanoma. Cancer Res. 2016; Aug. 76(16):4765–74.

103. Bivona TG, Doebele RC. A framework for understanding and targeting residual disease in oncogene-driven solid cancers. Nat Med. 2016; May. 22(5):472–8.

104. Tahmasebi-Birgani MJ, Teimoori A, Ghadiri A, Mansoury-Asl H, Danyaei A, Khanbabaei H. Fractionated radiotherapy might induce epithelial-mesenchymal transition and radioresistance in a cellular context manner. J Cell Biochem. 2019; May. 120(5):8601–10.

105. van den Berg J, Castricum KC, Meel MH, Goedegebuure RS, Lagerwaard FJ, Slotman BJ, et al. Development of transient radioresistance during fractionated irradiation in vitro. Radiother Oncol. 2020; Jul. 148:107–14.

106. Wilson GD, Thibodeau BJ, Fortier LE, Pruetz BL, Galoforo S, Marples B, et al. Cancer stem cell signaling during repopulation in head and neck cancer. Stem Cells Int. 2016; 2016:1894782.

107. Ge R, Wang Z, Cheng L. Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance. NPJ Precis Oncol. 2022; May. 6(1):31.

108. Folkman J. Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med. 1995; Jan. 1(1):27–31.

109. Cosse JP, Michiels C. Tumour hypoxia affects the responsiveness of cancer cells to chemotherapy and promotes cancer progression. Anticancer Agents Med Chem. 2008; Oct. 8(7):790–7.

110. Bertout JA, Patel SA, Simon MC. The impact of O2 availability on human cancer. Nat Rev Cancer. 2008; Dec. 8(12):967–75.

111. Bristow RG, Hill RP. Hypoxia and metabolism. Hypoxia, DNA repair and genetic instability. Nat Rev Cancer. 2008; Mar. 8(3):180–92.

112. Chen Z, Han F, Du Y, Shi H, Zhou W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023; Feb. 8(1):70.

113. Grimes DR, Partridge M. A mechanistic investigation of the oxygen fixation hypothesis and oxygen enhancement ratio. Biomed Phys Eng Express. 2015; Dec. 1(4):045209.

114. Schodel J, Oikonomopoulos S, Ragoussis J, Pugh CW, Ratcliffe PJ, Mole DR. High-resolution genome-wide mapping of HIF-binding sites by ChIP-seq. Blood. 2011; Jun. 117(23):e207–17.

115. Masoud GN, Li W. HIF-1α pathway: role, regulation and intervention for cancer therapy. Acta Pharm Sin B. 2015; Sep. 5(5):378–89.

116. Taylor CT, Scholz CC. The effect of HIF on metabolism and immunity. Nat Rev Nephrol. 2022; Sep. 18(9):573–87.

117. Aebersold DM, Burri P, Beer KT, Laissue J, Djonov V, Greiner RH, et al. Expression of hypoxia-inducible factor-1alpha: a novel predictive and prognostic parameter in the radiotherapy of oropharyngeal cancer. Cancer Res. 2001; Apr. 61(7):2911–6.

118. Schrijvers ML, van der Laan BF, de Bock GH, Pattje WJ, Mastik MF, Menkema L, et al. Overexpression of intrinsic hypoxia markers HIF1alpha and CA-IX predict for local recurrence in stage T1-T2 glottic laryngeal carcinoma treated with radiotherapy. Int J Radiat Oncol Biol Phys. 2008; Sep. 72(1):161–9.

119. Sapir L, Tzlil S. Talking over the extracellular matrix: how do cells communicate mechanically. Semin Cell Dev Biol. 2017; Nov. 71:99–105.

120. Weaver VM, Petersen OW, Wang F, Larabell CA, Briand P, Damsky C, et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J Cell Biol. 1997; Apr. 137(1):231–45.

121. He C, Wang L, Li L, Zhu G. Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors. Transl Oncol. 2021; Dec. 14(12):101231.

122. Fang Y, Liang S, Gao J, Wang Z, Li C, Wang R, et al. Extracellular matrix stiffness mediates radiosensitivity in a 3D nasopharyngeal carcinoma model. Cancer Cell Int. 2022; Nov. 22(1):364.

123. Li S, Sampson C, Liu C, Piao HL, Liu HX. Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities. Cell Commun Signal. 2023; Sep. 21(1):266.

124. Goel HL, Sayeed A, Breen M, Zarif MJ, Garlick DS, Leav I, et al. β1 integrins mediate resistance to ionizing radiation in vivo by inhibiting c-Jun amino terminal kinase 1. J Cell Physiol. 2013; Jul. 228(7):1601–9.

125. Ohlund D, Franklin O, Lundberg E, Lundin C, Sund M. Type IV collagen stimulates pancreatic cancer cell proliferation, migration, and inhibits apoptosis through an autocrine loop. BMC Cancer. 2013; Mar. 13:154.

126. Naba A, Clauser KR, Lamar JM, Carr SA, Hynes RO. Extracellular matrix signatures of human mammary carcinoma identify novel metastasis promoters. Elife. 2014; Mar. 3:e01308.

127. Erdogan B, Webb DJ. Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis. Biochem Soc Trans. 2017; Feb. 45(1):229–36.

128. Gabbiani G, Ryan GB, Majne G. Presence of modified fibroblasts in granulation tissue and their possible role in wound contraction. Experientia. 1971; May. 27(5):549–50.

129. Tomasek JJ, Gabbiani G, Hinz B, Chaponnier C, Brown RA. Myofibroblasts and mechano-regulation of connective tissue remodelling. Nat Rev Mol Cell Biol. 2002; May. 3(5):349–63.

130. Bautista-Hernandez LA, Gomez-Olivares JL, Buentello-Volante B, Bautista-de Lucio VM. Fibroblasts: the unknown sentinels eliciting immune responses against microorganisms. Eur J Microbiol Immunol (Bp). 2017; Aug. 7(3):151–7.

131. Li G, Larregina AT, Domsic RT, Stolz DB, Medsger TA, Lafyatis R, et al. Skin-resident effector memory CD8+CD28- T cells exhibit a profibrotic phenotype in patients with systemic sclerosis. J Invest Dermatol. 2017; May. 137(5):1042–50.

132. Taylor DK, Mittereder N, Kuta E, Delaney T, Burwell T, Dacosta K, et al. T follicular helper-like cells contribute to skin fibrosis. Sci Transl Med. 2018; Mar. 10(431):eaaf5307.

133. Hardee ME, Marciscano AE, Medina-Ramirez CM, Zagzag D, Narayana A, Lonning SM, et al. Resistance of glioblastoma-initiating cells to radiation mediated by the tumor microenvironment can be abolished by inhibiting transforming growth factor-β. Cancer Res. 2012; Aug. 72(16):4119–29.

134. Zhang D, Li L, Jiang H, Li Q, Wang-Gillam A, Yu J, et al. Tumor-stroma IL1β-IRAK4 feedforward circuitry drives tumor fibrosis, chemoresistance, and poor prognosis in pancreatic cancer. Cancer Res. 2018; Apr. 78(7):1700–12.

135. Liu L, Zhang Z, Zhou L, Hu L, Yin C, Qing D, et al. Cancer associated fibroblasts-derived exosomes contribute to radioresistance through promoting colorectal cancer stem cells phenotype. Exp Cell Res. 2020; Jun. 391(2):111956.

136. Qiao Y, Zhang C, Li A, Wang D, Luo Z, Ping Y, et al. IL6 derived from cancer-associated fibroblasts promotes chemoresistance via CXCR7 in esophageal squamous cell carcinoma. Oncogene. 2018; Feb. 37(7):873–83.

137. Zhang H, Yue J, Jiang Z, Zhou R, Xie R, Xu Y, et al. CAF-secreted CXCL1 conferred radioresistance by regulating DNA damage response in a ROS-dependent manner in esophageal squamous cell carcinoma. Cell Death Dis. 2017; May. 8(5):e2790.

138. Zhang H, Hua Y, Jiang Z, Yue J, Shi M, Zhen X, et al. Cancer-associated fibroblast-promoted LncRNA DNM3OS confers radioresistance by regulating DNA damage response in esophageal squamous cell carcinoma. Clin Cancer Res. 2019; Mar. 25(6):1989–2000.

139. Nicolas AM, Pesic M, Engel E, Ziegler PK, Diefenhardt M, Kennel KB, et al. Inflammatory fibroblasts mediate resistance to neoadjuvant therapy in rectal cancer. Cancer Cell. 2022; Feb. 40(2):168–84.e13.

140. Huang W, Zhang L, Yang M, Wu X, Wang X, Huang W, et al. Cancer-associated fibroblasts promote the survival of irradiated nasopharyngeal carcinoma cells via the NF-κB pathway. J Exp Clin Cancer Res. 2021; Mar. 40(1):87.

141. Demaria S, Ng B, Devitt ML, Babb JS, Kawashima N, Liebes L, et al. Ionizing radiation inhibition of distant untreated tumors (abscopal effect) is immune mediated. Int J Radiat Oncol Biol Phys. 2004; Mar. 58(3):862–70.

142. Nabrinsky E, Macklis J, Bitran J. A review of the abscopal effect in the era of immunotherapy. Cureus. 2022; Sep. 14(9):e29620.

143. Janopaul-Naylor JR, Shen Y, Qian DC, Buchwald ZS. The abscopal effect: a review of pre-clinical and clinical advances. Int J Mol Sci. 2021; Oct. 22(20):11061.

144. Buchbinder EI, Desai A. CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am J Clin Oncol. 2016; Feb. 39(1):98–106.

145. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat Commun. 2020; Jul. 11(1):3801.

146. Pal S, Dey D, Chakraborty BC, Nandi M, Khatun M, Banerjee S, et al. Diverse facets of MDSC in different phases of chronic HBV infection: Impact on HBV-specific T-cell response and homing. Hepatology. 2022; Sep. 76(3):759–74.

147. Hanson EM, Clements VK, Sinha P, Ilkovitch D, Ostrand-Rosenberg S. Myeloid-derived suppressor cells down-regulate L-selectin expression on CD4+ and CD8+ T cells. J Immunol. 2009; Jul. 183(2):937–44.

148. Ku AW, Muhitch JB, Powers CA, Diehl M, Kim M, Fisher DT, et al. Tumor-induced MDSC act via remote control to inhibit L-selectin-dependent adaptive immunity in lymph nodes. Elife. 2016; Dec. 5:e17375.

149. Cartwright AN, Suo S, Badrinath S, Kumar S, Melms J, Luoma A, et al. Immunosuppressive myeloid cells induce nitric oxide-dependent DNA damage and p53 pathway activation in CD8+ T cells. Cancer Immunol Res. 2021; Apr. 9(4):470–85.

150. Antonios JP, Soto H, Everson RG, Moughon D, Orpilla JR, Shin NP, et al. Immunosuppressive tumor-infiltrating myeloid cells mediate adaptive immune resistance via a PD-1/PD-L1 mechanism in glioblastoma. Neuro Oncol. 2017; Jun. 19(6):796–807.

151. Wang L, Jia B, Claxton DF, Ehmann WC, Rybka WB, Mineishi S, et al. VISTA is highly expressed on MDSCs and mediates an inhibition of T cell response in patients with AML. Oncoimmunology. 2018; Jul. 7(9):e1469594.

152. Sakuishi K, Jayaraman P, Behar SM, Anderson AC, Kuchroo VK. Emerging Tim-3 functions in antimicrobial and tumor immunity. Trends Immunol. 2011; Aug. 32(8):345–9.

153. Johnston RJ, Comps-Agrar L, Hackney J, Yu X, Huseni M, Yang Y, et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8(+) T cell effector function. Cancer Cell. 2014; Dec. 26(6):923–37.

154. Condamine T, Gabrilovich DI. Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trends Immunol. 2011; Jan. 32(1):19–25.

155. Conti I, Rollins BJ. CCL2 (monocyte chemoattractant protein-1) and cancer. Semin Cancer Biol. 2004; Jun. 14(3):149–54.

156. Borrego F, Ulbrecht M, Weiss EH, Coligan JE, Brooks AG. Recognition of human histocompatibility leukocyte antigen (HLA)-E complexed with HLA class I signal sequence-derived peptides by CD94/NKG2 confers protection from natural killer cell-mediated lysis. J Exp Med. 1998; Mar. 187(5):813–8.

157. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014; Jul. 41(1):49–61.

158. Curiel TJ, Coukos G, Zou L, Alvarez X, Cheng P, Mottram P, et al. Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival. Nat Med. 2004; Sep. 10(9):942–9.

159. Liu J, Zhang N, Li Q, Zhang W, Ke F, Leng Q, et al. Tumor-associated macrophages recruit CCR6+ regulatory T cells and promote the development of colorectal cancer via enhancing CCL20 production in mice. PLoS One. 2011; Apr. 6(4):e19495.

160. Schlecker E, Stojanovic A, Eisen C, Quack C, Falk CS, Umansky V, et al. Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth. J Immunol. 2012; Dec. 189(12):5602–11.

161. Yaseen MM, Abuharfeil NM, Darmani H, Daoud A. Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine. Open Biol. 2020; Sep. 10(9):200111.

162. Zheng Y, Cai Z, Wang S, Zhang X, Qian J, Hong S, et al. Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood. 2009; Oct. 114(17):3625–8.

163. Dhar S, Chakravarti M, Ganguly N, Saha A, Dasgupta S, Bera S, et al. High monocytic MDSC signature predicts multi-drug resistance and cancer relapse in non-Hodgkin lymphoma patients treated with R-CHOP. Front Immunol. 2024; Jan. 14:1303959.

164. Mantovani A, Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J Exp Med. 2015; Apr. 212(4):435–45.

165. Drew Y, Zenke FT, Curtin NJ. DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications. Nat Rev Drug Discov. 2025; Jan. 24(1):19–39.

166. Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009; Jul. 361(2):123–34.

167. Hong CR, Buckley CD, Wong WW, Anekal PV, Dickson BD, Bogle G, et al. Radiosensitisation of SCCVII tumours and normal tissues in mice by the DNA-dependent protein kinase inhibitor AZD7648. Radiother Oncol. 2022; Jan. 166:162–70.

168. Zenke FT, Zimmermann A, Sirrenberg C, Dahmen H, Kirkin V, Pehl U, et al. Pharmacologic inhibitor of DNA-PK, M3814, potentiates radiotherapy and regresses human tumors in mouse models. Mol Cancer Ther. 2020; May. 19(5):1091–101.

169. Samuels M, Falkenius J, Bar-Ad V, Dunst J, van Triest B, Yachnin J, et al. A phase 1 study of the DNA-PK inhibitor peposertib in combination with radiation therapy with or without cisplatin in patients with advanced head and neck tumors. Int J Radiat Oncol Biol Phys. 2024; Mar. 118(3):743–56.

170. Zeng L, Boggs DH, Xing C, Zhang Z, Anderson JC, Wajapeyee N, et al. Combining PARP and DNA-PK inhibitors with irradiation inhibits HPV-negative head and neck cancer squamous carcinoma growth. Front Genet. 2020; Sep. 11:1036.

171. Barker HE, Patel R, McLaughlin M, Schick U, Zaidi S, Nutting CM, et al. CHK1 inhibition radiosensitizes head and neck cancers to paclitaxel-based chemoradiotherapy. Mol Cancer Ther. 2016; Sep. 15(9):2042–54.

172. Zerp SF, Stoter TR, Hoebers FJ, van den Brekel MW, Dubbelman R, Kuipers GK, et al. Targeting anti-apoptotic Bcl-2 by AT-101 to increase radiation efficacy: data from in vitro and clinical pharmacokinetic studies in head and neck cancer. Radiat Oncol. 2015; Jul. 10:158.

173. Brands RC, Scheurer MJ, Hartmann S, Seher A, Kübler AC, Muller-Richter UD. Apoptosis-sensitizing activity of birinapant in head and neck squamous cell carcinoma cell lines. Oncol Lett. 2018; Mar. 15(3):4010–6.

174. Naz S, Leiker AJ, Choudhuri R, Preston O, Sowers AL, Gohain S, et al. Pharmacological inhibition of HSP90 radiosensitizes head and neck squamous cell carcinoma xenograft by inhibition of DNA damage repair, nucleotide metabolism, and radiation-induced tumor vasculogenesis. Int J Radiat Oncol Biol Phys. 2021; Aug. 110(5):1295–305.

175. Patel J, Nguyen SA, Ogretmen B, Gutkind JS, Nathan CA, Day T. mTOR inhibitor use in head and neck squamous cell carcinoma: a meta-analysis on survival, tumor response, and toxicity. Laryngoscope Investig Otolaryngol. 2020; Mar. 5(2):243–55.

176. Chuang FC, Wang CC, Chen JH, Hwang TZ, Yeh SA, Su YC. PI3k inhibitors (BKM120 and BYL719) as radiosensitizers for head and neck squamous cell carcinoma during radiotherapy. PLoS One. 2021; Jan. 16(1):e0245715.

177. Boustani J, Lecoester B, Baude J, Latour C, Adotevi O, Mirjolet C, et al. Anti-PD-1/Anti-PD-L1 drugs and radiation therapy: combinations and optimization strategies. Cancers (Basel). 2021; Sep. 13(19):4893.

178. Leidner R, Crittenden M, Young K, Xiao H, Wu Y, Couey MA, et al. Neoadjuvant immunoradiotherapy results in high rate of complete pathological response and clinical to pathological downstaging in locally advanced head and neck squamous cell carcinoma. J Immunother Cancer. 2021; May. 9(5):e002485.

179. Alterio D, Marvaso G, Ferrari A, Volpe S, Orecchia R, Jereczek-Fossa BA. Modern radiotherapy for head and neck cancer. Semin Oncol. 2019; Jun. 46(3):233–45.

180. Demaria S, Guha C, Schoenfeld J, Morris Z, Monjazeb A, Sikora A, et al. Radiation dose and fraction in immunotherapy: one-size regimen does not fit all settings, so how does one choose. J Immunother Cancer. 2021; Apr. 9(4):e002038.

181. Buchsbaum JC, Espey MG, Obcemea C, Capala J, Ahmed M, Prasanna PG, et al. Tumor heterogeneity research and innovation in biologically based radiation therapy from the national cancer institute radiation research program portfolio. J Clin Oncol. 2022; Jun. 40(17):1861–9.

182. Griffin RJ, Prise KM, McMahon SJ, Zhang X, Penagaricano J, Butterworth KT. History and current perspectives on the biological effects of high-dose spatial fractionation and high dose-rate approaches: GRID, Microbeam & FLASH radiotherapy. Br J Radiol. 2020; Sep. 93(1113):20200217.

183. Megahed RJ, Gholami S, Chien CL, Samanta S, Patel M, Kesaria AZ, et al. Spatially fractionated radiation therapy for bulky head and neck malignancies: A single institution experience. Int J Radiat Oncol Biol Phys. 2024; Oct. 120(2):e773.

184. Kim E, Yang K, Kim MS, Jang WI, Kim H, Lee DH, et al. Ultra-high dose rate FLASH effect on head and neck cancer cells and normal salivary gland in mice. Int J Radiat Oncol Biol Phys. 2022; Nov. 114(3):e507.

185. Vlastou E, Kougioumtzopoulou A, Platoni K, Georgakopoulos I, Lagopati N, Kouloulias V, et al. The emerging role of nanoparticles combined with either radiotherapy or hyperthermia in head and neck cancer: a current review. Cancers (Basel). 2025; Mar. 17(5):899.

186. Lu Q, Yan W, Zhu A, Tubin S, Mourad WF, Yang J. Combining spatially fractionated radiation therapy (SFRT) and immunotherapy opens new rays of hope for enhancing therapeutic ratio. Clin Transl Radiat Oncol. 2023; Oct. 44:100691.

187. Liu J, Zhou G, Pei H. The clinical prospect of FLASH radiotherapy. Radiat Med Prot. 2023; Dec. 4(4):190–96.

188. Epel B, Redler G, Pelizzari C, Tormyshev VM, Halpern HJ. Approaching oxygen-guided intensity-modulated radiation therapy. Adv Exp Med Biol. 2016; 876:185–93.

189. Gertsenshteyn I, Epel B, Giurcanu M, Barth E, Lukens J, Hall K, et al. Absolute oxygen-guided radiation therapy improves tumor control in three preclinical tumor models. Front Med (Lausanne). 2023; Oct. 10:1269689.

190. Yaromina A, Koi L, Schuitmaker L, van der Wiel AM, Dubois LJ, Krause M, et al. Overcoming radioresistance with the hypoxia-activated prodrug CP-506: a pre-clinical study of local tumour control probability. Radiother Oncol. 2023; Sep. 186:109738.

191. Bennett M, Feldmeier J, Smee R, Milross C. Hyperbaric oxygenation for tumour sensitisation to radiotherapy. Cochrane Database Syst Rev. 2005; Oct. (4):CD005007.