Exploration of Medicine

Table 1. Therapeutic strategies involving IL-12 in cancer immunotherapy

Strategy	Key features	Merits	Limitations	Key references
Monotherapy	Recombinant IL-12 or plasmid-based IL-12, often through intratumoral injection	-Potent activation of NK and T cells -Induces IFN-γ -Simple administration	-Severe systemic toxicity -Narrow therapeutic window -Lack of tumor specificity, off-target effects	[17, 39]
Combination therapy	IL-12 with chemotherapy, radiotherapy, or immune checkpoint inhibitors	-Synergistic antitumor effects -Can overcome resistance -Modulates tumor microenvironment	-Increased risk of systemic toxicity (mainly due to IFN-γ) -Complex dosing and management	[62]
Vector-based approach	Viral vectors, nanoparticles, or cell based delivery	-Localized sustained IL-12 expression -Reduced systemic toxicity -Enhanced immune activation	-Vector immunogenicity -Risk of insertional -Variable transfection efficiency	[39, 63]
Targeted delivery	Tumor-localized expression, gene therapy, oncolytic virus, immunocytokines	-Improved tumor specificity -Reduced off-target toxicity -Enhanced pharmacokinetics	-Incomplete tumor penetration -Potential immunogenicity of fusion protein -Off-tissue binding	[63]

Return to article view

IL-12: interleukin-12; NK: natural killer; IFN-γ: interferon-gamma

Declarations

Acknowledgments

The authors acknowledge the use of Paperpal (https://paperpal.com/), an AI-powered academic tool, for language editing and academic paraphrasing to enhance the clarity and readability of the manuscript. This assistance was limited to linguistic refinement, and the intellectual content, analysis, and interpretations remain entirely the authorsʼ own.

Author contributions

HAL: Conceptualization, Methodology, Writing—original draft, Writing—review & editing. AOR: Conceptualization, Methodology, Writing—original draft. AEO, ZAS, and WM: Data curation, Writing—original draft, Writing—review & editing. AOL and OJO: Writing—original draft, Writing—review & editing. RI and TAO: Writing—original draft, Supervision. All authors have read and approved the final manuscript.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

Publisher’s note

Open Exploration maintains a neutral stance on jurisdictional claims in published institutional affiliations and maps. All opinions expressed in this article are the personal views of the author(s) and do not represent the stance of the editorial team or the publisher.

References

Decker WK, da Silva RF, Sanabria MH, Angelo LS, Guimarães F, Burt BM, et al. Cancer Immunotherapy: Historical Perspective of a Clinical Revolution and Emerging Preclinical Animal Models. Front Immunol. 2017;8:829. [DOI] [PubMed] [PMC]

Oiseth SJ, Aziz MS. Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat. 2017;3:250–61. [DOI]

Tanigawa K, Redmond WL. Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy. Oncoimmunology. 2025;14:2452654. [DOI] [PubMed] [PMC]

Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature. 2017;541:321–30. [DOI] [PubMed]

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64. [DOI] [PubMed] [PMC]

June CH, OʼConnor RS, Kawalekar OU, Ghassemi S, Milone MC. CAR T cell immunotherapy for human cancer. Science. 2018;359:1361–5. [DOI] [PubMed]

Russell SJ, Peng K, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012;30:658–70. [DOI] [PubMed] [PMC]

Zitvogel L, Galluzzi L, Smyth MJ, Kroemer G. Mechanism of action of conventional and targeted anticancer therapies: reinstating immunosurveillance. Immunity. 2013;39:74–88. [DOI] [PubMed]

Sharma P, Allison JP. The future of immune checkpoint therapy. Science. 2015;348:56–61. [DOI] [PubMed]

10.

Postow MA, Sidlow R, Hellmann MD. Immune-Related Adverse Events Associated with Immune Checkpoint Blockade. N Engl J Med. 2018;378:158–68. [DOI] [PubMed]

11.

Joyce JA, Fearon DT. T cell exclusion, immune privilege, and the tumor microenvironment. Science. 2015;348:74–80. [DOI] [PubMed]

12.

Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell. 2017;168:707–23. [DOI] [PubMed] [PMC]

13.

Safaei S, Yari A, Pourbagherian O, Maleki LA. The role of cytokines in shaping the future of Cancer immunotherapy. Cytokine. 2025;189:156888. [DOI] [PubMed]

14.

Propper DJ, Balkwill FR. Harnessing cytokines and chemokines for cancer therapy. Nat Rev Clin Oncol. 2022;19:237–53. [DOI] [PubMed]

15.

Hamza T, Barnett JB, Li B. Interleukin 12 a key immunoregulatory cytokine in infection applications. Int J Mol Sci. 2010;11:789–806. [DOI] [PubMed] [PMC]

16.

Trinchieri G. Proinflammatory and immunoregulatory functions of interleukin-12. Int Rev Immunol. 1998;16:365–96. [DOI] [PubMed]

17.

Lasek W, Zagożdżon R, Jakobisiak M. Interleukin 12: still a promising candidate for tumor immunotherapy? Cancer Immunol Immunother. 2014;63:419–35. [DOI] [PubMed] [PMC]

18.

Lucas ML, Heller L, Coppola D, Heller R. IL-12 plasmid delivery by in vivo electroporation for the successful treatment of established subcutaneous B16.F10 melanoma. Mol Ther. 2002;5:668–75. [DOI] [PubMed]

19.

Floss DM, Moll JM, Scheller J. IL-12 and IL-23—Close Relatives with Structural Homologies but Distinct Immunological Functions. Cells. 2020;9:2184. [DOI] [PubMed] [PMC]

20.

Wojno EDT, Hunter CA, Stumhofer JS. The Immunobiology of the Interleukin-12 Family: Room for Discovery. Immunity. 2019;50:851–70. [DOI] [PubMed] [PMC]

21.

Ullrich KA, Schulze LL, Paap E, Müller TM, Neurath MF, Zundler S. Immunology of IL-12: An update on functional activities and implications for disease. EXCLI J. 2020;19:1563–89. [DOI] [PubMed] [PMC]

22.

Atkins MB, Robertson MJ, Gordon M, Lotze MT, DeCoste M, DuBois JS, et al. Phase I evaluation of intravenous recombinant human interleukin 12 in patients with advanced malignancies. Clin Cancer Res. 1997;3:409–17. [PubMed]

23.

Zhang C, Zhang J, Niu J, Zhou Z, Zhang J, Tian Z. Interleukin-12 improves cytotoxicity of natural killer cells via upregulated expression of NKG2D. Hum Immunol. 2008;69:490–500. [DOI] [PubMed]

24.

Zwirner NW, Ziblat A. Regulation of NK Cell Activation and Effector Functions by the IL-12 Family of Cytokines: The Case of IL-27. Front Immunol. 2017;8:25. [DOI] [PubMed] [PMC]

25.

Kondadasula SV, Roda JM, Parihar R, Yu J, Lehman A, Caligiuri MA, et al. Colocalization of the IL-12 receptor and FcγRIIIa to natural killer cell lipid rafts leads to activation of ERK and enhanced production of interferon-γ. Blood. 2008;111:4173–83. [DOI] [PubMed] [PMC]

26.

Zhang L, Kerkar SP, Yu Z, Zheng Z, Yang S, Restifo NP, et al. Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment. Mol Ther. 2011;19:751–9. [DOI] [PubMed] [PMC]

27.

Haddad EA, Senger LK, Takei F. An accessory role for B cells in the IL-12-induced activation of resting mouse NK cells. J Immunol. 2009;183:3608–15. [DOI] [PubMed]

28.

Horton BL, DʼSouza AD, Zagorulya M, McCreery CV, Abhiraman GC, Picton L, et al. Overcoming lung cancer immunotherapy resistance by combining nontoxic variants of IL-12 and IL-2. JCI Insight. 2023;8:e172728. [DOI] [PubMed] [PMC]

29.

Gao A, Lin Y, Chai Y, Han J, Wu L, Ye J. CXCL12/CXCR4 Axis Promotes the Chemotaxis and Phagocytosis of B Cells through the PI3K-AKT Signaling Pathway in an Early Vertebrate. J Immunol. 2024;213:1676–90. [DOI] [PubMed]

30.

Ni J, Miller M, Stojanovic A, Garbi N, Cerwenka A. Sustained effector function of IL-12/15/18–preactivated NK cells against established tumors. J Exp Med. 2012;209:2351–65. [DOI] [PubMed] [PMC]

31.

Sorensen EW, Gerber SA, Frelinger JG, Lord EM. IL-12 suppresses vascular endothelial growth factor receptor 3 expression on tumor vessels by two distinct IFN-γ–dependent mechanisms. J Immunol. 2010;184:1858–66. [DOI] [PubMed] [PMC]

32.

Tugues S, Burkhard SH, Ohs I, Vrohlings M, Nussbaum K, Berg JV, et al. New insights into IL-12-mediated tumor suppression. Cell Death Differ. 2015;22:237–46. [DOI] [PubMed] [PMC]

33.

Imagawa Y, Satake K, Kato Y, Tahara H, Tsukuda M. Antitumor and antiangiogenic effects of interleukin 12 gene therapy in murine head and neck carcinoma model. Auris Nasus Larynx. 2004;31:239–45. [DOI] [PubMed]

34.

Savid-Frontera C, Viano ME, Baez NS, Reynolds D, Matellon M, Young HA, et al. Safety levels of systemic IL-12 induced by cDNA expression as a cancer therapeutic. Immunotherapy. 2022;14:115–33. [DOI] [PubMed] [PMC]

35.

Song M, Ping Y, Zhang K, Yang L, Li F, Zhang C, et al. Low-Dose IFNγ Induces Tumor Cell Stemness in Tumor Microenvironment of Non-Small Cell Lung Cancer. Cancer Res. 2019;79:3737–48. [DOI] [PubMed]

36.

Chen H, Chou AS, Liu Y, Hsieh C, Kang C, Pang S, et al. Induction of metastatic cancer stem cells from the NK/LAK-resistant floating, but not adherent, subset of the UP-LN1 carcinoma cell line by IFN-γ. Lab Invest. 2011;91:1502–13. [DOI] [PubMed]

37.

Ding Q, Lu P, Xia Y, Ding S, Fan Y, Li X, et al. CXCL9: evidence and contradictions for its role in tumor progression. Cancer Med. 2016;5:3246–59. [DOI] [PubMed] [PMC]

38.

Aguilera-Durán G, Romo-Mancillas A. Computational Study of C-X-C Chemokine Receptor (CXCR)3 Binding with Its Natural Agonists Chemokine (C-X-C Motif) Ligand (CXCL)9, 10 and 11 and with Synthetic Antagonists: Insights of Receptor Activation towards Drug Design for Vitiligo. Molecules. 2020;25:4413. [DOI] [PubMed] [PMC]

39.

Nguyen KG, Vrabel MR, Mantooth SM, Hopkins JJ, Wagner ES, Gabaldon TA, et al. Localized Interleukin-12 for Cancer Immunotherapy. Front Immunol. 2020;11:575597. [DOI] [PubMed] [PMC]

40.

Voest EE, Kenyon BM, OʼReilly MS, Truitt G, DʼAmato RJ, Folkman J. Inhibition of angiogenesis in vivo by interleukin 12. J Natl Cancer Inst. 1995;87:581–6. [DOI] [PubMed]

41.

Zhou Y, Yoshida S, Kubo Y, Kobayashi Y, Nakama T, Yamaguchi M, et al. Interleukin-12 inhibits pathological neovascularization in mouse model of oxygen-induced retinopathy. Sci Rep. 2016;6:28140. [DOI] [PubMed] [PMC]

42.

Marin-Acevedo JA, Kimbrough EO, Lou Y. Next generation of immune checkpoint inhibitors and beyond. J Hematol Oncol. 2021;14:45. [DOI] [PubMed] [PMC]

43.

Rowshanravan B, Halliday N, Sansom DM. CTLA-4: a moving target in immunotherapy. Blood. 2018;131:58–67. [DOI] [PubMed] [PMC]

44.

Berg JV, Vrohlings M, Haller S, Haimovici A, Kulig P, Sledzinska A, et al. Intratumoral IL-12 combined with CTLA-4 blockade elicits T cell-mediated glioma rejection. J Exp Med. 2013;210:2803–11. [DOI] [PubMed] [PMC]

45.

Mendiratta SK, Quezada A, Matar M, Thull NM, Bishop JS, Nordstrom JL, et al. Combination of interleukin 12 and interferon alpha gene therapy induces a synergistic antitumor response against colon and renal cell carcinoma. Hum Gene Ther. 2000;11:1851–62. [DOI] [PubMed]

46.

Tanaka M, Saijo Y, Sato G, Suzuki T, Tazawa R, Satoh K, et al. Induction of antitumor immunity by combined immunogene therapy using IL-2 and IL-12 in low antigenic Lewis lung carcinoma. Cancer Gene Ther. 2000;7:1481–90. [DOI] [PubMed]

47.

Wigginton JM, Gruys E, Geiselhart L, Subleski J, Komschlies KL, Park JW, et al. IFN-γ and Fas/FasL are required for the antitumor and antiangiogenic effects of IL-12/pulse IL-2 therapy. J Clin Invest. 2001;108:51–62. [DOI] [PubMed] [PMC]

48.

Wigginton JM, Wiltrout RH. IL-12/IL-2 combination cytokine therapy for solid tumours: translation from bench to bedside. Expert Opin Biol Ther. 2002;2:513–24. [DOI] [PubMed]

49.

Teng MWL, Bowman EP, McElwee JJ, Smyth MJ, Casanova J, Cooper AM, et al. IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated inflammatory diseases. Nat Med. 2015;21:719–29. [DOI] [PubMed]

50.

Tamassia N, Arruda-Silva F, Wright HL, Moots RJ, Gardiman E, Bianchetto-Aguilera F, et al. Human neutrophils activated via TLR8 promote Th17 polarization through IL-23. J Leukoc Biol. 2019;105:1155–65. [DOI] [PubMed]

51.

Langowski JL, Zhang X, Wu L, Mattson JD, Chen T, Smith K, et al. IL-23 promotes tumour incidence and growth. Nature. 2006;442:461–5. [DOI] [PubMed]

52.

Habanjar O, Bingula R, Decombat C, Diab-Assaf M, Caldefie-Chezet F, Delort L. Crosstalk of Inflammatory Cytokines within the Breast Tumor Microenvironment. Int J Mol Sci. 2023;24:4002. [DOI] [PubMed] [PMC]

53.

Shah DD, Chorawala MR, Raghani NR, Patel R, Fareed M, Kashid VA, et al. Tumor microenvironment: recent advances in understanding and its role in modulating cancer therapies. Med Oncol. 2025;42:117. [DOI] [PubMed]

54.

Guo N, Wang W, Gong X, Gao L, Yang L, Yu W, et al. Study of recombinant human interleukin-12 for treatment of complications after radiotherapy for tumor patients. World J Clin Oncol. 2017;8:158–67. [DOI] [PubMed] [PMC]

55.

Colombo MP, Trinchieri G. Interleukin-12 in anti-tumor immunity and immunotherapy. Cytokine Growth Factor Rev. 2002;13:155–68. [DOI] [PubMed]

56.

Abbas Z, Rehman S. An Overview of Cancer Treatment Modalities. In: Shahzad HN, editor. Neoplasm. Rijeka: IntechOpen; 2018. [DOI]

57.

Mirlekar B, Pylayeva-Gupta Y. IL-12 Family Cytokines in Cancer and Immunotherapy. Cancers (Basel). 2021;13:167. [DOI] [PubMed] [PMC]

58.

Aldossary SA. Review on Pharmacology of Cisplatin: Clinical Use, Toxicity and Mechanism of Resistance of Cisplatin. Biomed Pharmacol J. 2019;12:7–15. [DOI]

59.

Jiao Y, Cao F, Liu H. Radiation-induced Cell Death and Its Mechanisms. Health Phys. 2022;123:376–86. [DOI] [PubMed] [PMC]

60.

Palata O, Podzimkova NH, Nedvedova E, Umprecht A, Sadilkova L, Jelinkova LP, et al. Radiotherapy in Combination With Cytokine Treatment. Front Oncol. 2019;9:367. [DOI] [PubMed] [PMC]

61.

Xu Y, Sun X, Tong Y. Interleukin-12 in multimodal tumor therapies for induction of anti-tumor immunity. Discov Oncol. 2024;15:170. [DOI] [PubMed] [PMC]

62.

Weiss JM, Subleski JJ, Wigginton JM, Wiltrout RH. Immunotherapy of cancer by IL-12-based cytokine combinations. Expert Opin Biol Ther. 2007;7:1705–21. [DOI] [PubMed] [PMC]

63.

Dong C, Tan D, Sun H, Li Z, Zhang L, Zheng Y, et al. Interleukin-12 Delivery Strategies and Advances in Tumor Immunotherapy. Curr Issues Mol Biol. 2024;46:11548–79. [DOI] [PubMed] [PMC]

64.

Barberio AE, Smith SG, Pires IS, Iyer S, Reinhardt F, Melo MB, et al. Layer-by-layer interleukin-12 nanoparticles drive a safe and effective response in ovarian tumors. Bioeng Transl Med. 2022;8:e10453. [DOI] [PubMed] [PMC]

65.

Jorgovanovic D, Song M, Wang L, Zhang Y. Roles of IFN-γ in tumor progression and regression: a review. Biomark Res. 2020;8:49. [DOI] [PubMed] [PMC]

66.

Cutrera J, King G, Jones P, Kicenuik K, Gumpel E, Xia X, et al. Safety and efficacy of tumor-targeted interleukin 12 gene therapy in treated and non-treated, metastatic lesions. Curr Gene Ther. 2015;15:44–54. [DOI] [PubMed] [PMC]

67.

Fukuhara H, Ino Y, Todo T. Oncolytic virus therapy: A new era of cancer treatment at dawn. Cancer Sci. 2016;107:1373–9. [DOI] [PubMed] [PMC]

68.

Wang H, Borlongan M, Hemminki A, Basnet S, Sah N, Kaufman HL, et al. Viral Vectors Expressing Interleukin 2 for Cancer Immunotherapy. Hum Gene Ther. 2023;34:878–95. [DOI] [PubMed] [PMC]

69.

Zhang H, Chen J, Zhang Q, Yu L, Li X, Wu S. Oncogenic viral antigens for engineered T cell immunotherapy: Challenges and opportunities. Med Adv. 2023;1:306–17. [DOI]

70.

Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124:188–95. [DOI] [PubMed] [PMC]

71.

DeBonis J, Veiseh O, Igoshin OA. Uncovering the interleukin-12 pharmacokinetic desensitization mechanism and its consequences with mathematical modeling. CPT Pharmacometrics Syst Pharmacol. 2025;14:217–28. [DOI] [PubMed] [PMC]

72.

Zheng H, Siddharth S, Parida S, Wu X, Sharma D. Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation. Cancers (Basel). 2021;13:3357. [DOI] [PubMed] [PMC]

73.

Neophytou CM, Panagi M, Stylianopoulos T, Papageorgis P. The Role of Tumor Microenvironment in Cancer Metastasis: Molecular Mechanisms and Therapeutic Opportunities. Cancers (Basel). 2021;13:2053. [DOI] [PubMed] [PMC]

74.

Yuan Z, Li Y, Zhang S, Wang X, Dou H, Yu X, et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol Cancer. 2023;22:48. [DOI] [PubMed] [PMC]

75.

Li Z, Hu L, Wang Y, Liu Q, Liu J, Long H, et al. Local administration of mRNA encoding cytokine cocktail confers potent anti-tumor immunity. Front Immunol. 2024;15:1455019. [DOI] [PubMed] [PMC]

76.

Kim HJ, Ji YR, Lee YM. Crosstalk between angiogenesis and immune regulation in the tumor microenvironment. Arch Pharm Res. 2022;45:401–16. [DOI] [PubMed] [PMC]

77.

Barba I, Carrillo-Bosch L, Seoane J. Targeting the Warburg Effect in Cancer: Where Do We Stand? Int J Mol Sci. 2024;25:3142. [DOI] [PubMed] [PMC]

78.

Portielje JEA, Lamers CHJ, Kruit WHJ, Sparreboom A, Bolhuis RLH, Stoter G, et al. Repeated administrations of interleukin (IL)-12 are associated with persistently elevated plasma levels of IL-10 and declining IFN-gamma, tumor necrosis factor-alpha, IL-6, and IL-8 responses. Clin Cancer Res. 2003;9:76–83. [PubMed]

79.

Robertson MJ, Soiffer RJ, Wolf SF, Manley TJ, Donahue C, Young D, et al. Response of human natural killer (NK) cells to NK cell stimulatory factor (NKSF): cytolytic activity and proliferation of NK cells are differentially regulated by NKSF. J Exp Med. 1992;175:779–88. [DOI] [PubMed] [PMC]

80.

Enk AH, Jonuleit H, Saloga J, Knop J. Dendritic cells as mediators of tumor-induced tolerance in metastatic melanoma. Int J Cancer. 1997;73:309–16. [DOI] [PubMed]

81.

Liu J, Cao S, Kim S, Chung EY, Homma Y, Guan X, et al. Interleukin-12: an update on its immunological activities, signaling and regulation of gene expression. Curr Immunol Rev. 2005;1:119–37. [DOI] [PubMed] [PMC]

82.

Goswami R, Subramanian G, Silayeva L, Newkirk I, Doctor D, Chawla K, et al. Gene Therapy Leaves a Vicious Cycle. Front Oncol. 2019;9:297. [DOI] [PubMed] [PMC]

83.

Sangro B, Melero I, Qian C, Prieto J. Gene therapy of cancer based on interleukin 12. Curr Gene Ther. 2005;5:573–81. [DOI] [PubMed]

84.

Johnson R, Roh C, Fischer-Lougheed J, Lees S. 1214 IL-12 vectors engineered to encode a functional p35-p40 heterodimer or a single p35 subunit for cancer immunotherapy. J Immunother Cancer. 2023;11:A1339. [DOI]

85.

Medrano G, Dolan MC, Stephens NT, McMickle A, Erf G, Radin D, et al. Efficient plant-based production of chicken interleukin-12 yields a strong immunostimulatory cytokine. J Interferon Cytokine Res. 2010;30:143–54. [DOI] [PubMed]

86.

Kwon TH, Seo JE, Kim J, Lee JH, Jang YS, Yang MS. Expression and secretion of the heterodimeric protein interleukin-12 in plant cell suspension culture. Biotechnol Bioeng. 2003;81:870–5. [DOI] [PubMed]

87.

Jayanthi S, Koppolu Bp, Smith SG, Jalah R, Bear J, Rosati M, et al. Efficient production and purification of recombinant human interleukin-12 (IL-12) overexpressed in mammalian cells without affinity tag. Protein Expr Purif. 2014;102:76–84. [DOI] [PubMed] [PMC]

88.

Cheng EM, Tsarovsky NW, Sondel PM, Rakhmilevich AL. Interleukin-12 as an in situ cancer vaccine component: a review. Cancer Immunol Immunother. 2022;71:2057–65. [DOI] [PubMed] [PMC]

89.

Xin Z, Qu S, Qu Y, Xu Y, Liu R, Sun D, et al. Emerging IL-12-based nanomedicine for cancer therapy. Nano Today. 2024;57:102331. [DOI]

90.

Yuzhalin AE, Kutikhin AG. Interleukin-12: clinical usage and molecular markers of cancer susceptibility. Growth Factors. 2012;30:176–91. [DOI] [PubMed]

91.

Farmer P, Frenk J, Knaul FM, Shulman LN, Alleyne G, Armstrong L, et al. Expansion of cancer care and control in countries of low and middle income: a call to action. Lancet. 2010;376:1186–93. [DOI] [PubMed]

92.

Zhang L, Norberg SM, Karimipour F, Davies JS, Kuznetsov A, Lassoued W, et al. Adoptive transfer of membrane-restricted IL-12-TCR T cells promotes antigen spreading and elimination of antigen-negative tumor variants. J Immunother Cancer. 2024;12:e009868. [DOI] [PubMed] [PMC]

93.

Hughson AL, Hannon G, Salama NA, Vrooman TG, Stockwell CA, Mills BN, et al. Integrating IL-12 mRNA nanotechnology with SBRT eliminates T cell exhaustion in preclinical models of pancreatic cancer. Mol Ther Nucleic Acids. 2024;35:102350. [DOI] [PubMed] [PMC]

94.

Ali MS, Ahn J, Espat NJ, Calvino AS, Koness J, Somasundar P, et al. Disparities in utilization of novel cancer therapies in advanced stage III and IV melanoma and variance in outcomes. Immunotherapy. 2025;17:37–46. [DOI] [PubMed]

95.

Ermer T, Canavan ME, Maduka RC, Li AX, Salazar MC, Kaminski MF, et al. Association Between Food and Drug Administration Approval and Disparities in Immunotherapy Use Among Patients With Cancer in the US. JAMA Netw Open. 2022;5:e2219535. [DOI] [PubMed] [PMC]

96.

Gupta A, Omeogu C, Islam JY, Joshi A, Zhang D, Braithwaite D, et al. Socioeconomic disparities in immunotherapy use among advanced-stage non-small cell lung cancer patients: analysis of the National Cancer Database. Sci Rep. 2023;13:8190. [DOI] [PubMed] [PMC]

97.

Osarogiagbon RU, Sineshaw HM, Unger JM, Acuña-Villaorduña A, Goel S. Immune-Based Cancer Treatment: Addressing Disparities in Access and Outcomes. Am Soc Clin Oncol Educ Book. 2021;41:1–13. [DOI] [PubMed]

98.

von Itzstein MS, Gwin ME, Gupta A, Gerber DE. Telemedicine and Cancer Clinical Research: Opportunities for Transformation. Cancer J. 2024;30:22–6. [DOI] [PubMed] [PMC]

99.

Cirella A, Luri-Rey C, Trani CAD, Teijeira A, Olivera I, Bolaños E, et al. Novel strategies exploiting interleukin-12 in cancer immunotherapy. Pharmacol Ther. 2022;239:108189. [DOI] [PubMed]

100.

Ruppl A, Kiesewetter D, Köll-Weber M, Lemazurier T, Süss R, Allmendinger A. Formulation screening of lyophilized mRNA-lipid nanoparticles. Int J Pharm. 2025;671:125272. [DOI] [PubMed]

101.

Jenei K, Aziz Z, Booth C, Cappello B, Ceppi F, de Vries EGE, et al. Cancer medicines on the WHO Model List of Essential Medicines: processes, challenges, and a way forward. Lancet Glob Health. 2022;10:e1860–6. [DOI] [PubMed]

102.

Beran D, Pedersen HB, Robertson J. Noncommunicable diseases, access to essential medicines and universal health coverage. Glob Health Action. 2019;12:1670014. [DOI] [PubMed] [PMC]

103.

Minnar CM, Lui G, Gulley JL, Schlom J, Gameiro SR. Preclinical and clinical studies of a tumor targeting IL-12 immunocytokine. Front Oncol. 2024;13:1321318. [DOI] [PubMed] [PMC]

104.

Jia Z, Ragoonanan D, Mahadeo KM, Gill J, Gorlick R, Shpal E, et al. IL12 immune therapy clinical trial review: Novel strategies for avoiding CRS-associated cytokines. Front Immunol. 2022;13:952231. [DOI] [PubMed] [PMC]

105.

Ren S, Deng J, Hong M, Ren Y, Fu H, Liu Y, et al. Ethical considerations of cellular immunotherapy for cancer. J Zhejiang Univ Sci B. 2019;20:23–31. [DOI] [PubMed] [PMC]

106.

Smith-Graziani D, Flowers CR. Understanding and Addressing Disparities in Patients With Hematologic Malignancies: Approaches for Clinicians. Am Soc Clin Oncol Educ Book. 2021;41:1–7. [DOI] [PubMed]

107.

Xu G, Li J, Zhang S, Cai J, Deng X, Wang Y, et al. Two-dimensional nano-biomaterials in regulating the tumor microenvironment for immunotherapy. Nano TransMed. 2024;3:100045. [DOI]

108.

Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019;120:6–15. [DOI] [PubMed] [PMC]

109.

Santollani L, Wittrup KD. Spatiotemporally programming cytokine immunotherapies through protein engineering. Immunol Rev. 2023;320:10–28. [DOI] [PubMed]

110.

Li S, Feng X, Wang J, He L, Wang C, Ding J, et al. Polymer nanoparticles as adjuvants in cancer immunotherapy. Nano Res. 2018;11:5769–86. [DOI]

111.

Thakur N, Thakur S, Chatterjee S, Das J, Sil PC. Nanoparticles as Smart Carriers for Enhanced Cancer Immunotherapy. Front Chem. 2020;8:597806. [DOI] [PubMed] [PMC]

112.

Zhang J, Wang S, Zhang D, He X, Wang X, Han H, et al. Nanoparticle-based drug delivery systems to enhance cancer immunotherapy in solid tumors. Front Immunol. 2023;14:1230893. [DOI] [PubMed] [PMC]

113.

Li J, Gu A, Tang N, Zhou J, Li C, Zengin G, et al. Vitcylation of Lysine: The Novel Mechanism of Vitamin C in Tumor Treatment. BIO Integr. 2025;6:1–6. [DOI]

114.

Yuan J, Hegde PS, Clynes R, Foukas PG, Harari A, Kleen TO, et al. Novel technologies and emerging biomarkers for personalized cancer immunotherapy. J Immunother Cancer. 2016;4:3. [DOI] [PubMed] [PMC]

115.

Powles T, Eder JP, Fine GD, Braiteh FS, Loriot Y, Cruz C, et al. MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer. Nature. 2014;515:558–62. [DOI] [PubMed]

116.

Liu S, Wu Y. Biomarker for personalized immunotherapy. Transl Lung Cancer Res. 2019;8:S308–17. [DOI] [PubMed] [PMC]

117.

Nash A, DeBonis J, Murungi D, Castillo B, Kim B, Hu F, et al. IL-12-producing cytokine factories induce precursor exhausted T cells and elimination of primary and metastatic tumors. J Immunother Cancer. 2025;13:e010685. [DOI] [PubMed] [PMC]

118.

Lai I, Swaminathan S, Baylot V, Mosley A, Dhanasekaran R, Gabay M, et al. Lipid nanoparticles that deliver IL-12 messenger RNA suppress tumorigenesis in MYC oncogene-driven hepatocellular carcinoma. J Immunother Cancer. 2018;6:125. [DOI] [PubMed] [PMC]

119.

Yang Z, Pietrobon V, Bobbin M, Stefanson O, Yang J, Goswami A, et al. Nanoscale, antigen encounter-dependent, IL-12 delivery by CAR T cells plus PD-L1 blockade for cancer treatment. J Transl Med. 2023;21:158. [DOI] [PubMed] [PMC]

120.

Remic T, Sersa G, Ursic K, Cemazar M, Kamensek U. Development of Tumor Cell-Based Vaccine with IL-12 Gene Electrotransfer as Adjuvant. Vaccines (Basel). 2020;8:111. [DOI] [PubMed] [PMC]

121.

Lee EHJ, Murad JP, Christian L, Gibson J, Yamaguchi Y, Cullen C, et al. Antigen-dependent IL-12 signaling in CAR T cells promotes regional to systemic disease targeting. Nat Commun. 2023;14:4737. [DOI] [PubMed] [PMC]

122.

Larson CP, Plamondon KM, Dubent L, Bicaba F, Bicaba A, Minh TH, et al. The Equity Tool for Valuing Global Health Partnerships. Glob Health Sci Pract. 2022;10:e2100316. [DOI] [PubMed] [PMC]

123.

Boyer B, Huber K, Zimlichman E, Saunders R, McClellan M, Kahn C, et al. Advancing the future of equitable access to health care: recommendations from international health care leaders. Health Aff Sch. 2024;2:qxae094. [DOI] [PubMed] [PMC]

124.

Dias MJS, Fernández P, Sousa P, Rocha Gonçalves F, Férnandez E. E-health effectiveness to increase patient adherence for immunotherapy: A cost-benefit study. Ann Oncol. 2019;30:v817. [DOI]

125.

Iyer HS, Kamanzi E, Mugunga JC, Finnegan K, Uwingabiye A, Shyaka E, et al. Improving district facility readiness: a 12-month evaluation of a data-driven health systems strengthening intervention in rural Rwanda. Glob Health Action. 2015;8:28365. [DOI] [PubMed] [PMC]

126.

Adunlin G, Ferreri SP, Dong J, Freeman MK. Immuno-Oncology Medicines: Policy Implications and Economic Considerations. Innov Pharm. 2019;10:10.24926/iip.v10i3.1799. [DOI] [PubMed] [PMC]

127.

Parmar A, Jiao T, Saluja R, Chan KKW. Value-based pricing: Toward achieving a balance between individual and population gains in health benefits. Cancer Med. 2020;9:94–103. [DOI] [PubMed] [PMC]

128.

Burdon A, Jaki T, Chen X, Mozgunov P, Zheng H, Baird R. Next generation clinical trials: Seamless designs and master protocols. arXiv:2405.06353 [Preprint]. 2024 [cited 2025 May 15]. Available from: https://arxiv.org/abs/2405.06353