REFERENCES

1. Yin Q, Wu L, Han L, et al. Immune-related adverse events of immune checkpoint inhibitors: a review. Front Immunol 2023;14:1167975.

2. Shiravand Y, Khodadadi F, Kashani SMA, et al. Immune checkpoint inhibitors in cancer therapy. Curr Oncol 2022;29:3044-60.

3. Johnson DB, Nebhan CA, Moslehi JJ, Balko JM. Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol 2022;19:254-67.

4. Mandal K, Barik GK, Santra MK. Overcoming resistance to anti-PD-L1 immunotherapy: mechanisms, combination strategies, and future directions. Mol Cancer 2025;24:246.

5. Zhang D, Zhao J, Zhang Y, Jiang H, Liu D. Revisiting immune checkpoint inhibitors: new strategies to enhance efficacy and reduce toxicity. Front Immunol 2024;15:1490129.

6. Alsaafeen BH, Ali BR, Elkord E. Resistance mechanisms to immune checkpoint inhibitors: updated insights. Mol Cancer 2025;24:20.

7. Dang BTN, Kwon TK, Lee S, Jeong JH, Yook S. Nanoparticle-based immunoengineering strategies for enhancing cancer immunotherapy. J Control Release 2024;365:773-800.

8. Lian S, Yang W, Zeng Y, Tang R, Wang K. Targeted nano-drug delivery systems for tumor immunotherapy. J Pharm Anal 2026;16:101408.

9. Ishida Y, Agata Y, Shibahara K, Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 1992;11:3887-95.

10. Lin X, Kang K, Chen P, et al. Regulatory mechanisms of PD-1/PD-L1 in cancers. Mol Cancer 2024;23:108.

11. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 2000;192:1027-34.

12. Jiang Y, Chen M, Nie H, Yuan Y. PD-1 and PD-L1 in cancer immunotherapy: clinical implications and future considerations. Hum Vaccin Immunother 2019;15:1111-22.

13. Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol 2018;71:189-94.

14. Munari E, Mariotti FR, Quatrini L, et al. PD-1/PD-L1 in cancer: pathophysiological, diagnostic and therapeutic aspects. Int J Mol Sci 2021;22:5123.

15. Sharpe AH, Wherry EJ, Ahmed R, Freeman GJ. The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection. Nat Immunol 2007;8:239-45.

16. Huang D, Wen W, Liu X, Li Y, Zhang JZH. Computational analysis of hot spots and binding mechanism in the PD-1/PD-L1 interaction. RSC Adv 2019;9:14944-56.

17. Paillon N, Mouro V, Dogniaux S, et al. PD-1 inhibits T cell actin remodeling at the immunological synapse independently of its signaling motifs. Sci Signal 2023;16:eadh2456.

18. Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 2017;168:707-23.

19. Doroshow DB, Bhalla S, Beasley MB, et al. PD-L1 as a biomarker of response to immune-checkpoint inhibitors. Nat Rev Clin Oncol 2021;18:345-62.

20. Bai R, Chen N, Li L, et al. Mechanisms of cancer resistance to immunotherapy. Front Oncol 2020;10:1290.

21. Monu NR, Frey AB. Myeloid-derived suppressor cells and anti-tumor T cells: a complex relationship. Immunol Invest 2012;41:595-613.

22. Ruan WS, Feng MX, Xu J, et al. Early activation of myeloid-derived suppressor cells participate in sepsis-induced immune suppression via PD-L1/PD-1 axis. Front Immunol 2020;11:1299.

23. Lu C, Redd PS, Lee JR, Savage N, Liu K. The expression profiles and regulation of PD-L1 in tumor-induced myeloid-derived suppressor cells. Oncoimmunology 2016;5:e1247135.

24. Ibrahim A, Mohamady Farouk Abdalsalam N, Liang Z, et al. MDSC checkpoint blockade therapy: a new breakthrough point overcoming immunosuppression in cancer immunotherapy. Cancer Gene Ther 2025;32:371-92.

25. Zhong C, Niu Y, Liu W, et al. S100A9 derived from chemoembolization-induced hypoxia governs mitochondrial function in hepatocellular carcinoma progression. Adv Sci 2022;9:e2202206.

26. Ikeda H, Old LJ, Schreiber RD. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev 2002;13:95-109.

27. Rieth J, Subramanian S. Mechanisms of intrinsic tumor resistance to immunotherapy. Int J Mol Sci 2018;19:1340.

28. Gao J, Shi LZ, Zhao H, et al. Loss of IFN-γ pathway genes in tumor cells as a mechanism of resistance to anti-CTLA-4 therapy. Cell 2016;167:397-404.e9.

29. Gato-Cañas M, Zuazo M, Arasanz H, et al. PDL1 signals through conserved sequence motifs to overcome interferon-mediated cytotoxicity. Cell Rep 2017;20:1818-29.

30. Doi T, Ishikawa T, Okayama T, et al. The JAK/STAT pathway is involved in the upregulation of PD-L1 expression in pancreatic cancer cell lines. Oncol Rep 2017;37:1545-54.

31. Li P, Huang T, Zou Q, et al. FGFR2 promotes expression of PD-L1 in colorectal cancer via the JAK/STAT3 signaling pathway. J Immunol 2019;202:3065-75.

32. Darnell JE Jr, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science 1994;264:1415-21.

33. Shin DS, Zaretsky JM, Escuin-Ordinas H, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov 2017;7:188-201.

34. Manguso RT, Pope HW, Zimmer MD, et al. In vivo CRISPR screening identifies Ptpn2 as a cancer immunotherapy target. Nature 2017;547:413-8.

35. Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol 2020;20:25-39.

36. Xue C, Chu Q, Shi Q, Zeng Y, Lu J, Li L. Wnt signaling pathways in biology and disease: mechanisms and therapeutic advances. Signal Transduct Target Ther 2025;10:106.

37. Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 2015;523:231-5.

38. Castagnoli L, Cancila V, Cordoba-Romero SL, et al. WNT signaling modulates PD-L1 expression in the stem cell compartment of triple-negative breast cancer. Oncogene 2019;38:4047-60.

39. Huang T, Li F, Cheng X, et al. Wnt inhibition sensitizes PD-L1 blockade therapy by overcoming bone marrow-derived myofibroblasts-mediated immune resistance in tumors. Front Immunol 2021;12:619209.

40. Wang H, Luo K, Zhan Y, Peng S, Fan S, Wang W. Role of β-catenin in PD-L1 expression of nasopharyngeal carcinoma. Heliyon 2023;9:e18130.

41. Sayaman RW, Saad M, Thorsson V, et al. Germline genetic contribution to the immune landscape of cancer. Immunity 2021;54:367-86.e8.

42. Haddadi N, Lin Y, Travis G, Simpson AM, Nassif NT, McGowan EM. PTEN/PTENP1: 'Regulating the regulator of RTK-dependent PI3K/Akt signalling', new targets for cancer therapy. Mol Cancer 2018;17:37.

43. Chen J, Jiang CC, Jin L, Zhang XD. Regulation of PD-L1: a novel role of pro-survival signalling in cancer. Ann Oncol 2016;27:409-16.

44. Bergholz JS, Wang Q, Wang Q, et al. PI3Kβ controls immune evasion in PTEN-deficient breast tumours. Nature 2023;617:139-46.

45. Matsushita H, Vesely MD, Koboldt DC, et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 2012;482:400-4.

46. Mittendorf EA, Philips AV, Meric-Bernstam F, et al. PD-L1 expression in triple-negative breast cancer. Cancer Immunol Res 2014;2:361-70.

47. Cui JW, Li Y, Yang Y, et al. Tumor immunotherapy resistance: revealing the mechanism of PD-1 / PD-L1-mediated tumor immune escape. Biomed Pharmacother 2024;171:116203.

48. Crane CA, Panner A, Murray JC, et al. PI(3) kinase is associated with a mechanism of immunoresistance in breast and prostate cancer. Oncogene 2009;28:306-12.

49. Peng W, Chen JQ, Liu C, et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov 2016;6:202-16.

50. Parsa AT, Waldron JS, Panner A, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nat Med 2007;13:84-8.

51. Zhao R, Song Y, Wang Y, et al. PD-1/PD-L1 blockade rescue exhausted CD8+ T cells in gastrointestinal stromal tumours via the PI3K/Akt/mTOR signalling pathway. Cell Prolif 2019;52:e12571.

52. Amornsupak K, Thongchot S, Thinyakul C, et al. HMGB1 mediates invasion and PD-L1 expression through RAGE-PI3K/AKT signaling pathway in MDA-MB-231 breast cancer cells. BMC Cancer 2022;22:578.

53. Guo F, Kong W, Li D, et al. M2-type tumor-associated macrophages upregulated PD-L1 expression in cervical cancer via the PI3K/AKT pathway. Eur J Med Res 2024;29:357.

54. Xu Y, Xiong J, Sun X, Gao H. Targeted nanomedicines remodeling immunosuppressive tumor microenvironment for enhanced cancer immunotherapy. Acta Pharm Sin B 2022;12:4327-47.

55. Tian M, Liu X, Pei H. Nanomaterial-based cancer immunotherapy: enhancing treatment strategies. Front Chem 2024;12:1492215.

56. Kateh Shamshiri M, Jaafari MR, Badiee A. Preparation of liposomes containing IFN-gamma and their potentials in cancer immunotherapy: in vitro and in vivo studies in a colon cancer mouse model. Life Sci 2021;264:118605.

57. Jesorka A, Orwar O. Liposomes: technologies and analytical applications. Annu Rev Anal Chem 2008;1:801-32.

58. Leduc PR, Wong MS, Ferreira PM, et al. Towards an in vivo biologically inspired nanofactory. Nat Nanotechnol 2007;2:3-7.

59. Liu Y, Crowe WN, Wang L, Petty WJ, Habib AA, Zhao D. Aerosolized immunotherapeutic nanoparticle inhalation potentiates PD-L1 blockade for locally advanced lung cancer. Nano Res 2023;16:5300-10.

60. Sun F, Zhu Q, Li T, et al. Regulating glucose metabolism with prodrug nanoparticles for promoting photoimmunotherapy of pancreatic cancer. Adv Sci 2021;8:2002746.

61. Zhang F, Stephan SB, Ene CI, Smith TT, Holland EC, Stephan MT. Nanoparticles that reshape the tumor milieu create a therapeutic window for effective T-cell therapy in solid malignancies. Cancer Res 2018;78:3718-30.

62. Lin YX, Wang Y, Ding J, et al. Reactivation of the tumor suppressor PTEN by mRNA nanoparticles enhances antitumor immunity in preclinical models. Sci Transl Med 2021;13:eaba9772.

63. Yu X, Fang C, Zhang K, Su C. Recent advances in nanoparticles-based platforms targeting the PD-1/PD-L1 pathway for cancer treatment. Pharmaceutics 2022;14:1581.

64. Jung JY, Ryu HJ, Lee SH, et al. siRNA nanoparticle targeting PD-L1 activates tumor immunity and abrogates pancreatic cancer growth in humanized preclinical model. Cells 2021;10:2734.

65. Wu Y, Gu W, Li J, Chen C, Xu ZP. Silencing PD-1 and PD-L1 with nanoparticle-delivered small interfering RNA increases cytotoxicity of tumor-infiltrating lymphocytes. Nanomedicine 2019;14:955-67.

66. Erel-Akbaba G, Carvalho LA, Tian T, et al. Radiation-induced targeted nanoparticle-based gene delivery for brain tumor therapy. ACS Nano 2019;13:4028-40.

67. Guan X, Lin L, Chen J, et al. Efficient PD-L1 gene silence promoted by hyaluronidase for cancer immunotherapy. J Control Release 2019;293:104-12.

68. Yin T, Fan Q, Hu F, et al. Engineered macrophage-membrane-coated nanoparticles with enhanced PD-1 expression induce immunomodulation for a synergistic and targeted antiglioblastoma activity. Nano Lett 2022;22:6606-14.

69. Younis M, Wu Y, Fang Q, Shan H, Huang X. Synergistic therapeutic antitumor effect of PD-1 blockade cellular vesicles in combination with Iguratimod and Rhodium nanoparticles. J Colloid Interface Sci 2023;649:929-42.

70. Xiao Z, Su Z, Han S, Huang J, Lin L, Shuai X. Dual pH-sensitive nanodrug blocks PD-1 immune checkpoint and uses T cells to deliver NF-κB inhibitor for antitumor immunotherapy. Sci Adv 2020;6:eaay7785.

71. Shi Y, Lammers T. Combining nanomedicine and immunotherapy. Acc Chem Res 2019;52:1543-54.

72. Chen IX, Chauhan VP, Posada J, et al. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci U S A 2019;116:4558-66.

73. Le HK, Graham L, Cha E, Morales JK, Manjili MH, Bear HD. Gemcitabine directly inhibits myeloid derived suppressor cells in BALB/c mice bearing 4T1 mammary carcinoma and augments expansion of T cells from tumor-bearing mice. Int Immunopharmacol 2009;9:900-9.

74. Kong M, Tang J, Qiao Q, et al. Biodegradable hollow mesoporous silica nanoparticles for regulating tumor microenvironment and enhancing antitumor efficiency. Theranostics 2017;7:3276-92.

75. Wang D, Wang T, Yu H, et al. Engineering nanoparticles to locally activate T cells in the tumor microenvironment. Sci Immunol 2019;4:eaau6584.

76. Joyce P, Allen CJ, Alonso MJ, et al. A translational framework to DELIVER nanomedicines to the clinic. Nat Nanotechnol 2024;19:1597-611.

77. Kon E, Ad-El N, Hazan-Halevy I, Stotsky-Oterin L, Peer D. Targeting cancer with mRNA-lipid nanoparticles: key considerations and future prospects. Nat Rev Clin Oncol 2023;20:739-54.

78. Ikeda-Imafuku M, Wang LL, Rodrigues D, Shaha S, Zhao Z, Mitragotri S. Strategies to improve the EPR effect: a mechanistic perspective and clinical translation. J Control Release 2022;345:512-36.

79. Cooley MB, Wegierak D, Perera R, et al. Assessing therapeutic nanoparticle accumulation in tumors using nanobubble-based contrast-enhanced ultrasound imaging. ACS Nano 2024;18:33181-96.

80. Chen BM, Cheng TL, Roffler SR. Polyethylene glycol immunogenicity: theoretical, clinical, and practical aspects of anti-polyethylene glycol antibodies. ACS Nano 2021;15:14022-48.

81. Estapé Senti M, de Jongh CA, Dijkxhoorn K, et al. Anti-PEG antibodies compromise the integrity of PEGylated lipid-based nanoparticles via complement. J Control Release 2022;341:475-86.

82. Szebeni J, Storm G, Ljubimova JY, et al. Applying lessons learned from nanomedicines to understand rare hypersensitivity reactions to mRNA-based SARS-CoV-2 vaccines. Nat Nanotechnol 2022;17:337-46.

83. Bitounis D, Jacquinet E, Rogers MA, Amiji MM. Strategies to reduce the risks of mRNA drug and vaccine toxicity. Nat Rev Drug Discov 2024;23:281-300.

84. Weber JS, Carlino MS, Khattak A, et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 2024;403:632-44.

85. Ribas A, Medina T, Kirkwood JM, et al. Overcoming PD-1 blockade resistance with CpG-A Toll-like receptor 9 agonist vidutolimod in patients with metastatic melanoma. Cancer Discov 2021;11:2998-3007.

86. Márquez-Rodas I, Dutriaux C, Saiag P, et al. BO-112 plus pembrolizumab for patients with anti-PD-1-resistant advanced melanoma: phase II clinical trial SPOTLIGHT-203. J Clin Oncol 2025;43:2806-15.

Cancer Drug Resistance
ISSN 2578-532X (Online)

Portico

All published articles will preserved here permanently:

https://www.portico.org/publishers/oae/

Portico

All published articles will preserved here permanently:

https://www.portico.org/publishers/oae/