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image of The Tumor Microenvironment: Impact on Tumor Growth, Metastasis, and Therapeutic Resistance: A Systematic Review

Abstract

Introduction

This systematic review assesses the role of the tumor microenvironment (TME) in cancer progression and therapy resistance by defining drug-microenvironment interactions and determining the molecular determinants in the TME that could help improve the efficacy of administered treatments and alleviate existing adverse effects.

Methods

This systematic review follows the PRISMA protocol and the PICOS selection framework to retrieve studies from PubMed/MEDLINE, Web of Science, Scopus, and the Cochrane Library. Only original human-related research published in English between 2008 and 2023 was used to explore the reciprocal relation between tumor cells and TME components. The ROBINS-I tool assessed the risk of bias.

Results

Out of 258 articles initially identified, 15 met the inclusion criteria for this review. The results showed that TMEs significantly influence treatment outcomes in cancer progression, metastasis, and drug resistance. Focusing on TMEs like CAFs, immune cells, and ECM enhances drug efficacy. The study highlighted potential strategies to improve drug delivery, suppress metastatic processes, and restore immune function, ultimately leading to better outcomes for cancer patients.

Discussion

Original evidence suggests that Cancer-Associated Fibroblasts (CAFs), immune cells, and Extracellular Matrix (ECM) contribute to therapeutic resistance and metastasis within the TME. They also promote metastasis by inducing Epithelial-Mesenchymal Transition (EMT) and affecting Cancer Stem Cell (CSC) populations. Moreover, the immunosuppressive TME consists of regulatory T cells and myeloid-derived suppressor cells that allow tumors to evade the immune system, a concern for immunotherapy.

Conclusion

The TME plays a vital role in cancer development, metastasis formation, and therapy failure. The perspectives for innovative ECM-modulating treatments and interventions targeting the direct interactions between TME and cancer cells can be revolutionary and suggest better outcomes for treatment-naïve and refractory cancers. Future research should use these results as inputs to apply clinical and therapy studies to enhance cancer management outcomes.

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2025-09-29
2025-11-02

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References

  1. Motofei I.G. Biology of cancer, from cellular and molecular mechanisms to developmental processes and adaptation. Semin. Cancer Biol. 2021 76 59 67 10.1016/j.semcancer.2021.10.003 34695580
    [Google Scholar]
  2. Rahman M.M. Islam F. Mim S.A. Multifunctional therapeutic approach of nanomedicines against inflammation in cancer and aging. J. Nanomater. 2022 2022 1 19 10.1155/2022/4217529
    [Google Scholar]
  3. Yip H.Y.K. Papa A. Signaling pathways in cancer: Therapeutic targets, combinatorial treatments, and new developments. Cells 2021 10 3 659 10.3390/cells10030659 33809714
    [Google Scholar]
  4. Bertram J.S. The molecular biology of cancer. Mol. Aspects Med. 2000 21 6 167 223 10.1016/S0098‑2997(00)00007‑8 11173079
    [Google Scholar]
  5. Arneth B. Tumor microenvironment. Medicina 2019 56 1 15 10.3390/medicina56010015 31906017
    [Google Scholar]
  6. Chen X. Song E. The theory of tumor ecosystem. Cancer Commun. 2022 42 7 587 608 10.1002/cac2.12316 35642770
    [Google Scholar]
  7. Lüönd F. Tiede S. Christofori G. Breast cancer as an example of tumour heterogeneity and tumour cell plasticity during malignant progression. Br. J. Cancer 2021 125 2 164 175 10.1038/s41416‑021‑01328‑7 33824479
    [Google Scholar]
  8. Mao X. Xu J. Wang W. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: New findings and future perspectives. Mol. Cancer 2021 20 1 131 10.1186/s12943‑021‑01428‑1 34635121
    [Google Scholar]
  9. Hilmi M. Nicolle R. Bousquet C. Neuzillet C. Cancer-associated fibroblasts: Accomplices in the tumor immune evasion. Cancers 2020 12 10 2969 10.3390/cancers12102969 33066357
    [Google Scholar]
  10. Haider M.T. Ridlmaier N. Smit D.J. Taipaleenmäki H. Interleukins as mediators of the tumor cell-bone cell crosstalk during the initiation of breast cancer bone metastasis. Int. J. Mol. Sci. 2021 22 6 2898 10.3390/ijms22062898 33809315
    [Google Scholar]
  11. Dominiak A. Chełstowska B. Olejarz W. Nowicka G. Communication in the cancer microenvironment as a target for therapeutic interventions. Cancers 2020 12 5 1232 10.3390/cancers12051232 32422889
    [Google Scholar]
  12. Yuan Z. Li Y. Zhang S. Extracellular matrix remodeling in tumor progression and immune escape: From mechanisms to treatments. Mol. Cancer 2023 22 1 48 10.1186/s12943‑023‑01744‑8 36906534
    [Google Scholar]
  13. Fabian K.L. Storkus W.J. Immunotherapeutic targeting of tumor-associated blood vessels. Adv. Exp. Med. Biol. 2017 1036 191 211 10.1007/978‑3‑319‑67577‑0_13 29275473
    [Google Scholar]
  14. Al-Ostoot F.H. Salah S. Khamees H.A. Khanum S.A. Tumor angiogenesis: Current challenges and therapeutic opportunities. Cancer Treat. Res. Commun. 2021 28 100422 10.1016/j.ctarc.2021.100422 34147821
    [Google Scholar]
  15. Amini A. Masoumi Moghaddam S. Morris D.L. Pourgholami M.H. The critical role of vascular endothelial growth factor in tumor angiogenesis. Curr. Cancer Drug Targets 2012 12 1 23 43 10.2174/156800912798888956 22111836
    [Google Scholar]
  16. Lee W.S. Yang H. Chon H.J. Kim C. Combination of anti-angiogenic therapy and immune checkpoint blockade normalizes vascular-immune crosstalk to potentiate cancer immunity. Exp. Mol. Med. 2020 52 9 1475 1485 10.1038/s12276‑020‑00500‑y 32913278
    [Google Scholar]
  17. Yousefi M. Nosrati R. Salmaninejad A. Dehghani S. Shahryari A. Saberi A. Organ-specific metastasis of breast cancer: Molecular and cellular mechanisms underlying lung metastasis. Cell. Oncol. 2018 41 2 123 140 10.1007/s13402‑018‑0376‑6 29568985
    [Google Scholar]
  18. Zhuyan J. Chen M. Zhu T. Critical steps to tumor metastasis: Alterations of tumor microenvironment and extracellular matrix in the formation of pre-metastatic and metastatic niche. Cell Biosci. 2020 10 1 89 10.1186/s13578‑020‑00453‑9 32742634
    [Google Scholar]
  19. Arvelo F. Sojo F. Cotte C. Tumour progression and metastasis. Ecancermedicalscience 2016 10 617 10.3332/ecancer.2016.617 26913068
    [Google Scholar]
  20. Dongre A. Weinberg R.A. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 2019 20 2 69 84 10.1038/s41580‑018‑0080‑4 30459476
    [Google Scholar]
  21. Singh M. Yelle N. Venugopal C. Singh S.K. EMT: Mechanisms and therapeutic implications. Pharmacol. Ther. 2018 182 80 94 10.1016/j.pharmthera.2017.08.009 28834698
    [Google Scholar]
  22. Guo S. Deng C.X. Effect of stromal cells in tumor microenvironment on metastasis initiation. Int. J. Biol. Sci. 2018 14 14 2083 2093 10.7150/ijbs.25720 30585271
    [Google Scholar]
  23. Kim S.K. Cho S.W. The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment. Front. Pharmacol. 2022 13 868695 10.3389/fphar.2022.868695 35685630
    [Google Scholar]
  24. Marigo I. Dolcetti L. Serafini P. Zanovello P. Bronte V. Tumor‐induced tolerance and immune suppression by myeloid derived suppressor cells. Immunol. Rev. 2008 222 1 162 179 10.1111/j.1600‑065X.2008.00602.x 18364001
    [Google Scholar]
  25. Mitra A. Kumar A. Amdare N.P. Pathak R. Current landscape of cancer immunotherapy: Harnessing the immune arsenal to overcome immune evasion. Biology 2024 13 5 307 10.3390/biology13050307 38785789
    [Google Scholar]
  26. Sui X. Chen R. Wang Z. Autophagy and chemotherapy resistance: A promising therapeutic target for cancer treatment. Cell Death Dis. 2013 4 10 e838 10.1038/cddis.2013.350 24113172
    [Google Scholar]
  27. Baudino T. Targeted cancer therapy: The next generation of cancer treatment. Curr. Drug Discov. Technol. 2015 12 1 3 20 10.2174/1570163812666150602144310 26033233
    [Google Scholar]
  28. Saleh R. Elkord E. Acquired resistance to cancer immunotherapy: Role of tumor-mediated immuno-suppression. Semin. Cancer Biol. 2020 65 13 27 10.1016/j.semcancer.2019.07.017 31362073
    [Google Scholar]
  29. Henke E. Nandigama R. Ergün S. Extracellular matrix in the tumor microenvironment and its impact on cancer therapy. Front. Mol. Biosci. 2020 6 160 10.3389/fmolb.2019.00160 32118030
    [Google Scholar]
  30. Kalli M. Poskus M.D. Stylianopoulos T. Zervantonakis I.K. Beyond matrix stiffness: Targeting force-induced cancer drug resistance. Trends Cancer 2023 9 11 937 954 10.1016/j.trecan.2023.07.006 37558577
    [Google Scholar]
  31. Overchuk M. Zheng G. Overcoming obstacles in the tumor microenvironment: Recent advancements in nanoparticle delivery for cancer theranostics. Biomaterials 2018 156 217 237 10.1016/j.biomaterials.2017.10.024 29207323
    [Google Scholar]
  32. Zhang M. Zhou K. Wang Z. A subpopulation of luminal progenitors secrete pleiotrophin to promote angiogenesis and metastasis in inflammatory breast cancer. Cancer Res. 2024 84 11 1781 1798 10.1158/0008‑5472.CAN‑23‑2640 38507720
    [Google Scholar]
  33. Ebbesen P Pettersen EO Gorr TA Taking advantage of tumor cell adaptations to hypoxia for developing new tumor markers and treatment strategies. J Enzyme Inhib Med Chem 2009 24 sup1): 1-39.(Suppl. 1 10.1080/14756360902784425 19330638
    [Google Scholar]
  34. Son B. Lee S. Youn H. Kim E. Kim W. Youn B. The role of tumor microenvironment in therapeutic resistance. Oncotarget 2017 8 3 3933 3945 10.18632/oncotarget.13907 27965469
    [Google Scholar]
  35. Sun Y. Tumor microenvironment and cancer therapy resistance. Cancer Lett. 2016 380 1 205 215 10.1016/j.canlet.2015.07.044 26272180
    [Google Scholar]
  36. Baghban R. Roshangar L. Jahanban-Esfahlan R. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Commun. Signal. 2020 18 1 59 10.1186/s12964‑020‑0530‑4 32264958
    [Google Scholar]
  37. Neophytou C.M. Panagi M. Stylianopoulos T. Papageorgis P. The role of tumor microenvironment in cancer metastasis: Molecular mechanisms and therapeutic opportunities. Cancers 2021 13 9 2053 10.3390/cancers13092053 33922795
    [Google Scholar]
  38. Meng L. Zheng Y. Liu H. Fan D. The tumor microenvironment: A key player in multidrug resistance in cancer. Oncologie 2024 26 1 41 58 10.1515/oncologie‑2023‑0459
    [Google Scholar]
  39. Nallasamy P. Nimmakayala R.K. Parte S. Are A.C. Batra S.K. Ponnusamy M.P. Tumor microenvironment enriches the stemness features: The architectural event of therapy resistance and metastasis. Mol. Cancer 2022 21 1 225 10.1186/s12943‑022‑01682‑x 36550571
    [Google Scholar]
  40. Lorusso G. Rüegg C. The tumor microenvironment and its contribution to tumor evolution toward metastasis. Histochem. Cell Biol. 2008 130 6 1091 1103 10.1007/s00418‑008‑0530‑8 18987874
    [Google Scholar]
  41. Wang Q. Shao X. Zhang Y. Role of tumor microenvironment in cancer progression and therapeutic strategy. Cancer Med. 2023 12 10 11149 11165 10.1002/cam4.5698 36807772
    [Google Scholar]
  42. Kilmister E.J. Koh S.P. Weth F.R. Gray C. Tan S.T. Cancer metastasis and treatment resistance: Mechanistic insights and therapeutic targeting of cancer stem cells and the tumor microenvironment. Biomedicines 2022 10 11 2988 10.3390/biomedicines10112988 36428556
    [Google Scholar]
  43. Feig C. Jones J.O. Kraman M. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti–PD-L1 immunotherapy in pancreatic cancer. Proc. Natl. Acad. Sci. USA 2013 110 50 20212 20217 10.1073/pnas.1320318110 24277834
    [Google Scholar]
  44. Walker C. Mojares E. Del Río Hernández A. Role of extracellular matrix in development and cancer progression. Int. J. Mol. Sci. 2018 19 10 3028 10.3390/ijms19103028 30287763
    [Google Scholar]
  45. Lv L. Pan K. Li X. The accumulation and prognosis value of tumor infiltrating IL-17 producing cells in esophageal squamous cell carcinoma. PLoS One 2011 6 3 e18219 10.1371/journal.pone.0018219 21483813
    [Google Scholar]
  46. Tietze J.K. Wilkins D.E.C. Sckisel G.D. Delineation of antigen-specific and antigen-nonspecific CD8+ memory T-cell responses after cytokine-based cancer immunotherapy. Blood 2012 119 13 3073 3083 10.1182/blood‑2011‑07‑369736 22251483
    [Google Scholar]
  47. Andreu P. Johansson M. Affara N.I. FcRgamma activation regulates inflammation-associated squamous carcinogenesis. Cancer Cell 2010 17 2 121 134 10.1016/j.ccr.2009.12.019 20138013
    [Google Scholar]
  48. de Visser K.E. Joyce J.A. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 2023 41 3 374 403 10.1016/j.ccell.2023.02.016 36917948
    [Google Scholar]
  49. Zheng P.P. Li J. Kros J.M. Breakthroughs in modern cancer therapy and elusive cardiotoxicity: Critical research‐practice gaps, challenges, and insights. Med. Res. Rev. 2018 38 1 325 376 10.1002/med.21463 28862319
    [Google Scholar]
  50. Bhat G.R. Sethi I. Sadida H.Q. Cancer cell plasticity: From cellular, molecular, and genetic mechanisms to tumor heterogeneity and drug resistance. Cancer Metastasis Rev. 2024 43 1 197 228 10.1007/s10555‑024‑10172‑z 38329598
    [Google Scholar]
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The Tumor Microenvironment: Impact on Tumor Growth, Metastasis, and Therapeutic Resistance: A Systematic Review
Bentham Science Publishers ; https://doi.org/10.2174/0115665240388282250903221303
/content/journals/cmm/10.2174/0115665240388282250903221303
/content/journals/cmm/10.2174/0115665240388282250903221303
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  • Article Type:     Review Article
Keywords: metastasis ; Immune Evasion ; therapeutic resistance ; Extracellular Matrix (ECM) ; Cancer-associated Fibroblasts (CAFs) ; Tumor Microenvironment (TME)

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