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image of The Role of Immunotherapy in Lung Cancer Treatment: Current Strategies, Future Directions, and Insights into Metastasis and Immune Microenvironment

Abstract

Lung cancer is a leading cause of mortality worldwide. Immunotherapy has emerged as a potentially effective strategy, as traditional medicines have shown minimal success. This review investigates the current state of immunotherapy for lung cancer treatment, focusing on its mechanisms, clinical applications, strategies, and future directions. This study focuses on the different characteristics of non-small and small-cell lung cancer to emphasize the need for targeted treatment strategies. In non-small cell lung cancer, immune checkpoint inhibitors that target PD-1, PD-L1, and CTLA-4 have shown a strong therapeutic benefit and increased survival rates. The complex interactions among tumor cells, immune cells, and the tumor microenvironment significantly impact the outcome of immunotherapy. The determination of predicting biomarkers and conquering resistance requires an understanding of the tumor microenvironment. This study addresses a range of immunotherapeutic strategies, such as immune modulators, monoclonal antibodies, and cancer vaccines. The combination approaches are being explored to enhance treatment effectiveness and address resistance mechanisms that integrate immunotherapy with other modalities. Despite advancements, challenges still exist. The identification of reliable biomarkers, regulating immune-related adverse effects, and the overcoming of limitations in treating metastatic disease require more investigation. Future research directions should include exploring the immune microenvironment, developing personalized treatment strategies based on tumor profiles, and integrating new technologies for patient screening. Immunotherapy holds immense potential to modify lung cancer treatment and enhance clinical results.

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2025-01-06
2025-06-29
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References

  1. W Liu Ganoderma triterpenoids attenuate tumour angiogenesis in lung cancer tumour-bearing nude mice Pharmaceutical Biology 2020 58 1 1070 1077
    [Google Scholar]
  2. Pandi A Mamo G Getachew D Kitila F Kalappan V Dhiravidamani S. A brief review on lung cancer. IJPRHS 2016 4 1 907 914
    [Google Scholar]
  3. Xing P.Y. Zhu Y.X. Wang L. Hui Z.G. Liu S.M. Ren J.S. Zhang Y. Song Y. Liu C.C. Huang Y.C. Liao X.Z. Xing X.J. Wang D.B. Yang L. Du L.B. Liu Y.Q. Zhang Y.Z. Liu Y.Y. Wei D.H. Zhang K. Shi J.F. Qiao Y.L. Chen W.Q. Li J.L. Dai M. LuCCRES Group What are the clinical symptoms and physical signs for non‐small cell lung cancer before diagnosis is made? A nation‐wide multicenter 10‐year retrospective study in China. Cancer Med. 2019 8 8 4055 4069 10.1002/cam4.2256 31150167
    [Google Scholar]
  4. SH Lee Chemotherapy for lung cancer in the era of personalized medicine Tuberc Respir Dis (Seoul) 2019 82 3 179 189
    [Google Scholar]
  5. Kim H.C. Choi C.M. Current status of immunotherapy for lung cancer and future perspectives. Tuberc. Respir. Dis. (Seoul) 2020 83 1 14 19 10.4046/trd.2019.0039 31905428
    [Google Scholar]
  6. Siegel R.L. Miller K.D. Jemal A. Cancer statistics, 2018. CA Cancer J. Clin. 2018 68 1 7 30 10.3322/caac.21442 29313949
    [Google Scholar]
  7. Gonzalez H. Hagerling C. Werb Z. Roles of the immune system in cancer: From tumor initiation to metastatic progression. Genes Dev. 2018 32 19-20 1267 1284 10.1101/gad.314617.118 30275043
    [Google Scholar]
  8. Mamdani H. Matosevic S. Khalid A.B. Durm G. Jalal S.I. Immunotherapy in lung cancer: Current landscape and future directions. Front. Immunol. 2022 13 823618 10.3389/fimmu.2022.823618 35222404
    [Google Scholar]
  9. Rizvi N.A. Mazières J. Planchard D. Stinchcombe T.E. Dy G.K. Antonia S.J. Horn L. Lena H. Minenza E. Mennecier B. Otterson G.A. Campos L.T. Gandara D.R. Levy B.P. Nair S.G. Zalcman G. Wolf J. Souquet P.J. Baldini E. Cappuzzo F. Chouaid C. Dowlati A. Sanborn R. Lopez-Chavez A. Grohe C. Huber R.M. Harbison C.T. Baudelet C. Lestini B.J. Ramalingam S.S. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): A phase 2, single-arm trial. Lancet Oncol. 2015 16 3 257 265 10.1016/S1470‑2045(15)70054‑9 25704439
    [Google Scholar]
  10. Immunotherapy for lung cancer 2016 Available from: https://onlinelibrary.wiley.com/doi/full/10.1111/resp.12789
  11. A Lahiri Lung cancer immunotherapy: Progress, pitfalls, and promises Mol Cancer 2023 22 1 40
    [Google Scholar]
  12. Arcaro A. Targeted therapies for small cell lung cancer: Where do we stand? Crit. Rev. Oncol. Hematol. 2015 95 2 154 164 10.1016/j.critrevonc.2015.03.001 25800975
    [Google Scholar]
  13. Zhan X. Feng S. Zhou X. Liao W. Zhao B. Yang Q. Tan Q. Shen J. Immunotherapy response and microenvironment provide biomarkers of immunotherapy options for patients with lung adenocarcinoma. Front. Genet. 2022 13 1047435 10.3389/fgene.2022.1047435 36386793
    [Google Scholar]
  14. What is immunotherapy? 2024 Available from: https://www.cancer.net/navigating-cancer-care/how-cancer-treated/immunotherapy-and-vaccines/what-immunotherapy
  15. Aros C.J. Paul M.K. Pantoja C.J. Bisht B. Meneses L.K. Vijayaraj P. Sandlin J.M. France B. Tse J.A. Chen M.W. Shia D.W. Rickabaugh T.M. Damoiseaux R. Gomperts B.N. High-throughput drug screening identifies a potent wnt inhibitor that promotes airway basal stem cell Homeostasis. Cell Rep. 2020 30 7 2055 2064.e5 10.1016/j.celrep.2020.01.059 32075752
    [Google Scholar]
  16. Wang W. Liu H. Li G. What’s the difference between lung adenocarcinoma and lung squamous cell carcinoma? Evidence from a retrospective analysis in a cohort of Chinese patients. Front. Endocrinol. (Lausanne) 2022 13 947443 10.3389/fendo.2022.947443 36105402
    [Google Scholar]
  17. Zappa Cecilia Non-small cell lung cancer: Current treatment and future advances Transl Lung Cancer Res 2016 5 3 288 300
    [Google Scholar]
  18. Bordas A. Cedillo J.L. Arnalich F. Esteban-Rodriguez I. Guerra-Pastrián L. de Castro J. Martín-Sánchez C. Atienza G. Fernández-Capitan C. Rios J.J. Montiel C. Expression patterns for nicotinic acetylcholine receptor subunit genes in smoking-related lung cancers. Oncotarget 2017 8 40 67878 67890 10.18632/oncotarget.18948 28978081
    [Google Scholar]
  19. American society for radiation oncology (ASTRO) 2024 Available from: https://www.astro.org/
  20. Pernot S. Evrard S. Khatib A.M. The give-and-take interaction between the tumor microenvironment and immune cells regulating tumor progression and repression. Front. Immunol. 2022 13 850856 10.3389/fimmu.2022.850856 35493456
    [Google Scholar]
  21. Altorki N.K. Markowitz G.J. Gao D. Port J.L. Saxena A. Stiles B. McGraw T. Mittal V. The lung microenvironment: An important regulator of tumour growth and metastasis. Nat. Rev. Cancer 2019 19 1 9 31 10.1038/s41568‑018‑0081‑9 30532012
    [Google Scholar]
  22. Stankovic B. Bjørhovde H.A.K. Skarshaug R. Aamodt H. Frafjord A. Müller E. Hammarström C. Beraki K. Bækkevold E.S. Woldbæk P.R. Helland Å. Brustugun O.T. Øynebråten I. Corthay A. Immune cell composition in human non-small cell lung cancer. Front. Immunol. 2019 9 3101 10.3389/fimmu.2018.03101 30774636
    [Google Scholar]
  23. Bai R. Cui J. Development of immunotherapy strategies targeting tumor microenvironment is fiercely ongoing. Front. Immunol. 2022 13 890166 10.3389/fimmu.2022.890166 35833121
    [Google Scholar]
  24. Hasegawa T. Suzuki H. Yamaura T. Muto S. Okabe N. Osugi J. Hoshino M. Higuchi M. Ise K. Gotoh M. Prognostic value of peripheral and local forkhead box P3+ regulatory T cells in patients with non-small-cell lung cancer. Mol. Clin. Oncol. 2014 2 5 685 694 10.3892/mco.2014.299 25054031
    [Google Scholar]
  25. Kinoshita T. Ishii G. Hiraoka N. Hirayama S. Yamauchi C. Aokage K. Hishida T. Yoshida J. Nagai K. Ochiai A. Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma. Cancer Sci. 2013 104 4 409 415 10.1111/cas.12099 23305175
    [Google Scholar]
  26. Ling Y. Wang J. Wang L. Hou J. Qian P. Xiang-dong W. Roles of CEACAM1 in cell communication and signaling of lung cancer and other diseases. Cancer Metastasis Rev. 2015 34 2 347 357 10.1007/s10555‑015‑9569‑x 26081722
    [Google Scholar]
  27. Fridman G. Grieser E. Hill R. Khuddus N. Bersani T. Slonim C. Propranolol for the treatment of orbital infantile hemangiomas. Ophthal. Plast. Reconstr. Surg. 2011 27 3 190 194 10.1097/IOP.0b013e318201d344 21283032
    [Google Scholar]
  28. Mandl S.J. Rountree R.B. Dalpozzo K. Do L. Lombardo J.R. Schoonmaker P.L. Dirmeier U. Steigerwald R. Giffon T. Laus R. Delcayre A. Immunotherapy with MVA-BN®-HER2 induces HER-2-specific Th1 immunity and alters the intratumoral balance of effector and regulatory T cells. Cancer Immunol. Immunother. 2012 61 1 19 29 10.1007/s00262‑011‑1077‑4 21822917
    [Google Scholar]
  29. Lahmar Q Keirsse J Laoui D Movahedi K Van Overmeire E Van Ginderachter JA Tissue-resident versus monocyte-derived macrophages in the tumor microenvironment Biochim Biophys Acta 2016 1865 1 23 34
    [Google Scholar]
  30. Almatroodi S.A. McDonald C.F. Darby I.A. Pouniotis D.S. Characterization of M1/M2 tumour-associated Macrophages (TAMs) and Th1/Th2 cytokine profiles in patients with NSCLC. Cancer Microenviron. 2016 9 1 1 11 10.1007/s12307‑015‑0174‑x 26319408
    [Google Scholar]
  31. Fridlender Z.G. Sun J. Kim S. Kapoor V. Cheng G. Ling L. Worthen G.S. Albelda S.M. Polarization of tumor-associated neutrophil phenotype by TGF-β: “N1” versus “N2” TAN. Cancer Cell 2009 16 3 183 194 10.1016/j.ccr.2009.06.017 19732719
    [Google Scholar]
  32. David C.J. Huang Y.H. Chen M. Su J. Zou Y. Bardeesy N. Iacobuzio-Donahue C.A. Massagué J. TGF-β Tumor Suppression through a Lethal EMT. Cell 2016 164 5 1015 1030 10.1016/j.cell.2016.01.009 26898331
    [Google Scholar]
  33. Yang T. Xiong Y. Zeng Y. Wang Y. Zeng J. Liu J. Xu S. Li L.S. Current status of immunotherapy for non-small cell lung cancer. Front. Pharmacol. 2022 13 989461 10.3389/fphar.2022.989461 36313314
    [Google Scholar]
  34. Das J.M. Das J.M. Immunotherapy. Neuro-Oncology Explained Through Multiple Choice Questions. Springer International Publishing Cham 2023 109 115 10.1007/978‑3‑031‑13253‑7_10
    [Google Scholar]
  35. Ap S. Pv C.M.A. Pu S. Targeted therapies for the treatment of non-small-cell lung cancer: Monoclonal antibodies and biological inhibitors Hum Vaccin Immunother 2017 13 4 843 853
    [Google Scholar]
  36. What are the benefits of using monoclonal antibodies? 2017 Available from: https://www.proteogenix.science/monoclonal-antibody-production/faqs-monoclonal-antibodies/benefits-monoclonal-antibodies/#:~:text=Monoclonal%20antibodies%20are%20one%20of%20the%20most%20successful%20biotherapeutic%20drugs,patient%20survival%20and%20well%2Dbeing.
  37. Zhong S. Cui Y. Liu Q. Chen S. CAR-T cell therapy for lung cancer: A promising but challenging future. J. Thorac. Dis. 2020 12 8 4516 4521 10.21037/jtd.2020.03.118 32944366
    [Google Scholar]
  38. M Binnewies Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med 2018 24 541 550
    [Google Scholar]
  39. Godfrey D.I. Le Nours J. Andrews D.M. Uldrich A.P. Rossjohn J. Unconventional T. Unconventional T cell targets for cancer immunotherapy. Immunity 2018 48 3 453 473 10.1016/j.immuni.2018.03.009 29562195
    [Google Scholar]
  40. Bruchard M. Ghiringhelli F. Deciphering the roles of innate lymphoid cells in cancer. Front. Immunol. 2019 10 656 10.3389/fimmu.2019.00656 31024531
    [Google Scholar]
  41. Leko V. Rosenberg S.A. Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell 2020 38 4 454 472 10.1016/j.ccell.2020.07.013 32822573
    [Google Scholar]
  42. Gou Qian PD-L1 degradation pathway and immunotherapy for cancer. Cell Death Dis 2020 11 955
    [Google Scholar]
  43. Iwai Yoshiko Cancer immunotherapies targeting the PD-1 signaling pathway. J Biomed Sci 2017 24 26
    [Google Scholar]
  44. Role of the tumor immune microenvironment in tumor immunotherapy (Review) 2021 Available from: https://www.spandidos-publications.com/10.3892/ol.2021.13171
  45. Zhai Y. Moosavi R. Chen M. Immune checkpoints, a novel class of therapeutic targets for autoimmune diseases. Front. Immunol. 2021 12 645699 10.3389/fimmu.2021.645699 33968036
    [Google Scholar]
  46. Tang T. Huang X. Zhang G. Hong Z. Bai X. Liang T. Advantages of targeting the tumor immune microenvironment over blocking immune checkpoint in cancer immunotherapy. Signal Transduct. Target. Ther. 2021 6 1 72 10.1038/s41392‑020‑00449‑4 33608497
    [Google Scholar]
  47. Malhotra J. Jabbour S.K. Aisner J. Current state of immunotherapy for non-small cell lung cancer. Transl. Lung Cancer Res. 2007 6 2 196 211 10.21037/tlcr.2017.03.01 28529902
    [Google Scholar]
  48. Adhikary Subhamay Current technologies and future perspectives in immunotherapy towards a clinical oncology approach Biomedicines 2024 12 1 217
    [Google Scholar]
  49. Wuerdemann Nora LAG-3, TIM-3 and VISTA expression on tumor-infiltrating lymphocytes in oropharyngeal squamous cell carcinoma—potential biomarkers for targeted therapy concepts Int. J. Mol. Sci. 2021 22 1 379
    [Google Scholar]
  50. Cai Letong Targeting LAG-3, TIM-3, and TIGIT for cancer immunotherapy Journal of Hematology & Oncology 2023 16 101
    [Google Scholar]
  51. Sobhani Navid CTLA-4 in regulatory T cells for cancer immunotherapy Cancers 2021 13 6 1440
    [Google Scholar]
  52. Zabeti Touchaei Arefeh MicroRNAs as regulators of immune checkpoints in cancer immunotherapy: Targeting PD-1/PD-L1 and CTLA-4 pathways. Cancer Cell Int 2024 24 102
    [Google Scholar]
  53. Safi M. Ahmed H. Al-Azab M. Xia Y. Shan X. Al-radhi M. Al-danakh A. Shopit A. Liu J. PD-1/PDL-1 inhibitors and cardiotoxicity; molecular, etiological and management outlines. J. Adv. Res. 2021 29 45 54 10.1016/j.jare.2020.09.006 33842004
    [Google Scholar]
  54. Wojtukiewicz M.Z. Rek M.M. Karpowicz K. Górska M. Polityńska B. Wojtukiewicz A.M. Moniuszko M. Radziwon P. Tucker S.C. Honn K.V. Inhibitors of immune checkpoints—PD-1, PD-L1, CTLA-4—new opportunities for cancer patients and a new challenge for internists and general practitioners. Cancer Metastasis Rev. 2021 40 3 949 982 10.1007/s10555‑021‑09976‑0 34236546
    [Google Scholar]
  55. Jin S. Sun Y. Liang X. Gu X. Ning J. Xu Y. Chen S. Pan L. Emerging new therapeutic antibody derivatives for cancer treatment. Signal Transduct. Target. Ther. 2022 7 1 39 10.1038/s41392‑021‑00868‑x 35132063
    [Google Scholar]
  56. Therapeutic strategies for EGFR-mutated non-small cell lung cancer patients with osimertinib resistance 2024 Available from: https://link.springer.com/article/10.1186/s13045-022-01391-4
  57. Rajdev K. Siddiqui A.H. Ibrahim U. Patibandla P. Khan T. El-Sayegh D. An unusually aggressive large cell carcinoma of the lung: undiagnosed until autopsy 2018 Available from: https://www.cureus.com/articles/10689-an-unusually-aggressive-large-cell-carcinoma-of-the-lung-undiagnosed-until-autopsy
  58. Understanding the tumor microenvironment for effective immunotherapy 2020 Available from: https://onlinelibrary.wiley.com/doi/full/10.1002/med.21765
  59. Wang Z. Kim J. Zhang P. Galvan Achi J.M. Jiang Y. Rong L. Current therapy and development of therapeutic agents for lung cancer. Cell Insight 2022 1 2 100015 10.1016/j.cellin.2022.100015 37193130
    [Google Scholar]
  60. Okobi T.J. Uhomoibhi T.O. Akahara D.E. Odoma V.A. Sanusi I.A. Okobi O.E. Immune checkpoint inhibitors as a treatment option for bladder cancer: Current evidence 2023 Available from: https://www.cureus.com/articles/160204-immune-checkpoint-inhibitors-as-a-treatment-option-for-bladder-cancer-current-evidence
  61. Maffuid Kaitlyn Decoding the complexity of immune–cancer cell interactions: Empowering the future of cancer immunotherapy Cancers 2023 15 16 4188
    [Google Scholar]
  62. S.L Gupta Immunotherapy: An alternative promising therapeutic approach against cancers Mol Biol Rep 2022 49 9903 9913
    [Google Scholar]
  63. Stewart J.M. Keselowsky B.G. Combinatorial drug delivery approaches for immunomodulation. Adv. Drug Deliv. Rev. 2017 114 161 174 10.1016/j.addr.2017.05.013 28532690
    [Google Scholar]
  64. Qu Jialin Mechanism and potential predictive biomarkers of immune checkpoint inhibitors in NSCLC B&P 2020 127 109996
    [Google Scholar]
  65. H.H Popper Progression and metastasis of lung cancer Cancer Metastasis Rev 2016 35 75 91
    [Google Scholar]
  66. Punekar S.R. Shum E. Grello C.M. Lau S.C. Velcheti V. Immunotherapy in non-small cell lung cancer: Past, present, and future directions. Front. Oncol. 2022 12 877594 10.3389/fonc.2022.877594 35992832
    [Google Scholar]
  67. Haibe Y. Kreidieh M. El Hajj H. Khalifeh I. Mukherji D. Temraz S. Shamseddine A. Resistance mechanisms to anti-angiogenic therapies in cancer. Front. Oncol. 2020 10 221 10.3389/fonc.2020.00221 32175278
    [Google Scholar]
  68. MSC Li Developments in targeted therapy & immunotherapy—how non-small cell lung cancer management will change in the next decade: A narrative review Ann Transl Med 2023 11 358
    [Google Scholar]
  69. Li Shenduo Emerging targeted therapies in advanced non-small-cell lung cancer Cancers 2023 15 11 2899
    [Google Scholar]
  70. Giuliano S. Pagès G. Mechanisms of resistance to anti-angiogenesis therapies. Biochimie 2013 95 6 1110 1119 10.1016/j.biochi.2013.03.002 23507428
    [Google Scholar]
  71. Javed Ansari Mohammad Cancer combination therapies by angiogenesis inhibitors; a comprehensive review Cell Commun Signal 2022 20 49
    [Google Scholar]
  72. Tzeng Hong-Tai Tumor vasculature as an emerging pharmacological target to promote anti-tumor immunity Int. J. Mol. Sci. 2023 24 5 4422
    [Google Scholar]
  73. H Mumtaz Exploring alternative approaches to precision medicine through genomics and artificial intelligence - a systematic review Front Med (Lausanne) 2023 10 1227168
    [Google Scholar]
  74. S Yu HLA loss of heterozygosity-mediated discordant responses to immune checkpoint blockade in squamous cell lung cancer with renal metastasis Immunotherapy 2020 13 195 200
    [Google Scholar]
  75. Abbasian M.H. Ardekani A.M. Sobhani N. Roudi R. The role of genomics and proteomics in lung cancer early detection and treatment. Cancers 2022 14 20 5144 10.3390/cancers14205144 36291929
    [Google Scholar]
  76. Pandey P. Khan F. Qari H.A. Upadhyay T.K. Alkhateeb A.F. Oves M. Revolutionization in cancer therapeutics via targeting major immune checkpoints PD-1, PD-L1 and CTLA-4. Pharmaceuticals 2022 15 3 335 10.3390/ph15030335 35337133
    [Google Scholar]
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