Prerpints.org logo
Preprint
Review

Unraveling the Hidden Impact of Tumor Microenvironment: Insights into Novel Therapeutic Strategies for Oncology in Tanzania: Integrated Review

Altmetrics

Downloads

155

Views

70

Comments

0

This version is not peer-reviewed

Novel Discoveries in Oncology

Submitted:

13 April 2023

Posted:

14 April 2023

You are already at the latest version

Alerts
Abstract
The tumor microenvironment (TME) plays a critical role in cancer progression and treatment outcomes. Despite advances in cancer research, many therapeutic strategies have failed to provide the desired clinical outcomes. In this integrated review, aimed to explore the role of TME in cancer biology and develop novel therapeutic strategies that target not only cancer cells but also the surrounding microenvironment. Study conducted a comprehensive literature search using PubMed, Embase, and Web of Science databases for articles published between 2016 and 2022. Inclusion of articles that discussed the impact of TME on cancer development and progression, as well as articles that proposed novel therapeutic strategies targeting the TME. The analysis of the literature revealed that the TME plays a crucial role in cancer development and progression by promoting cancer cell survival, angiogenesis, invasion, and metastasis, and by interfering with the efficacy of cancer therapies. The TME is composed of a complex network of non-cancerous cells, extracellular matrix components, and signaling molecules that interact with cancer cells. Several novel therapeutic strategies have been proposed based on the modulation of TME components. One of the most promising approaches is the use of immunotherapy, which aims to enhance the immune system's ability to recognize and attack cancer cells. Immunotherapy drugs such as checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and immune-stimulatory monoclonal antibodies have been approved for the treatment of different cancer types. These approaches have shown promising results in preclinical studies and clinical trials. The TME plays a critical role in cancer development and progression, and targeting its components represents a promising avenue for cancer therapy. Novel therapeutic strategies such as immunotherapy, extracellular matrix-targeting drugs, and nanoparticle-based therapies have shown promising results in preclinical studies and clinical trials. However, further research is needed to identify the most effective strategies and to overcome the challenges associated with TME targeting.
Keywords: 
Subject: Medicine and Pharmacology  -   Oncology and Oncogenics

1. Introduction

Cancer is a leading cause of death worldwide, and its impact on public health and healthcare systems is substantial. It is a complex and multifactorial disease that affects millions of people worldwide. According to the Global Cancer Statistics 2018 report, there were an estimated 18.1 million new cases of cancer and 9.6 million deaths from cancer in 2018(Bray et al., 2018). Despite significant advances in cancer diagnosis and treatment, the overall survival rates for many types of cancer remain low. Therefore, there is an urgent need for the development of innovative and effective therapeutic strategies for oncology (Bray et al., 2018; Hanahan & Coussens, 2012; Pucci et al., 2019).
In recent years, there has been growing recognition of the importance of the tumor microenvironment (TME) in the development, progression, and treatment of cancer. The TME is a complex network of non-cancerous cells, extracellular matrix (ECM), and signaling molecules that interact with cancer cells to promote tumor growth, invasion, and metastasis (Hanahan & Coussens, 2012). There has been growing interest in targeting the TME as a promising therapeutic approach for cancer treatment. Inhibition of specific signaling pathways involved in TME-mediated tumor growth and metastasis, or modulation of immune response in the TME, have shown promising results in preclinical and clinical studies (Binnewies et al., 2018; Joyce & Fearon, 2015). Novel targets within the TME, such as cancer-associated fibroblasts (CAFs) or immune checkpoint inhibitors, have also been identified as potential therapeutic options (Klemm & Joyce, 2015; Sharma et al., 2017).
The TME plays a significant role in shaping tumor behavior and treatment response. Its complexity interplay between cancer cells and the surrounding non-cancerous cells, extracellular matrix, and other components within the tumor's vicinity Accumulating evidence suggests that the TME can promote tumor growth, angiogenesis, and immune evasion, as well as contribute to the development of resistance to chemotherapy and targeted therapies (Binnewies et al., 2018; Quail & Joyce, 2017). The interactions between tumor cells and the TME can create a favorable environment for tumor cells to thrive and evade immune surveillance, leading to tumor progression and metastasis (Baghban et al., 2020; Pernot et al., 2022; Quail & Joyce, 2013).
Furthermore, the TME can also modulate the response to cancer therapy. For example, the presence of specific immune cells in the TME, such as tumor-associated macrophages (TAMs) or regulatory T cells (Tregs), can impair anti-tumor immune responses and limit the efficacy of immunotherapies (Chen & Mellman, 2017). The TME can also contribute to drug resistance by promoting the activation of signaling pathways that protect tumor cells from the cytotoxic effects of chemotherapy or targeted therapies (Lu et al., 2017).
Several studies have shown that the TME is a dynamic and heterogeneous environment that plays a critical role in cancer progression and treatment resistance (Egeblad et al., 2010; Quail & Joyce, 2013). The TME comprises various cell types, including immune cells, fibroblasts, endothelial cells, and adipocytes, which secrete cytokines, growth factors, and extracellular matrix (ECM) components that promote tumor cell survival and proliferation (Quail & Joyce, 2017). The TME also influences cancer cell behavior through epigenetic modifications, metabolic reprogramming, and immune evasion (Binnewies et al., 2018; Khalil & Friedl, 2010).
Despite significant advancements in cancer therapies, including surgery, chemotherapy, radiation therapy, and immunotherapy, many cancer patients still face challenges such as treatment resistance, relapse, and adverse effects (Binnewies et al., 2018; Khalil & Friedl, 2010). It is increasingly evident that understanding and targeting the tumor microenvironment could be a promising approach to overcome these challenges and develop novel therapeutic strategies for oncology(Sounni et al., 2014; Sounni & Noel, 2013; Wang et al., 2017).
For example, targeting vascular endothelial growth factor (VEGF) or its receptors has been successful in inhibiting tumor angiogenesis and improving the efficacy of chemotherapy in several cancer types, such as colorectal cancer and non-small cell lung cancer(Ferrara et al., 2004; Jain et al., 2006). In addition, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, which block the PD-1/PD-L1 pathway, have shown remarkable success in treating a variety of cancers, including melanoma, lung cancer, and bladder cancer (Pardoll, 2012; Ribas & Wolchok, 2018). These immunotherapies work by unleashing the body's immune system to recognize and attack cancer cells, and have revolutionized cancer treatment for certain patients(Ribas & Wolchok, 2018).
Other approaches targeting the TME include strategies to disrupt the interactions between tumor cells and their surrounding stromal cells, such as CAFs, which are known to promote tumor growth and metastasis (Klemm & Joyce, 2015). Inhibition of specific signaling pathways involved in the TME, such as the transforming growth factor-β (TGF-β) pathway or the hedgehog pathway, have also shown promise in preclinical studies as potential therapeutic (Biancur et al., 2021; Tauriello et al., 2018).
Furthermore, combination therapies that target both tumor cells and the TME have shown synergistic effects in preclinical and clinical studies. For example, combination of chemotherapy with immunotherapies or targeted therapies has demonstrated improved treatment outcomes in certain cancers (M. Hegde et al., 2016; P. S. Hegde et al., 2016; Kanz et al., 2016).
However, targeting the TME also presents challenges, including the complexity and heterogeneity of the TME, potential off-target effects on normal tissues, and the risk of developing resistance to TME-targeting therapies (Baghban et al., 2020; Khalaf et al., 2021; Kutoka et al., 2022; Runa et al., 2017). This review identifies gaps in knowledge and propose potential research directions for future investigations.

2. Methods and Material

This research utilized an integrated review methodology, which involves synthesizing and analyzing existing literature from multiple sources to provide a comprehensive overview of the research topic. A systematic literature search will be conducted using electronic databases, such as PubMed, Scopus, and Web of Science, as well as relevant journals and conference proceedings. Keywords and Medical Subject Headings (MeSH) terms related to tumor microenvironment, novel therapeutic strategies, and oncology will be used to identify relevant articles. Studies that meet the inclusion criteria, including those that focus on the tumor microenvironment, provide insights into novel therapeutic strategies, and are related to oncology, will be included in the integrated review. The quality and rigor of the included studies will be assessed using appropriate tools, such as the Joanna Briggs Institute (JBI) critical appraisal checklist for different study designs (Joanna Briggs Institute, 2019).

3. Results

The study findings show that, Tumor microenvironment (TME) plays a crucial role in cancer progression and treatment response. Studies have shown that the complex interactions between tumor cells, immune cells, stromal cells, and extracellular matrix components in the TME can promote tumor growth, angiogenesis, and metastasis, and contribute to therapeutic resistance.
TME can influence the efficacy of conventional cancer therapies, such as chemotherapy, radiation therapy, and immunotherapy. For example, the presence of immune-suppressive cells and molecules in the TME can hinder the anti-tumor immune response and limit the effectiveness of immunotherapies. Understanding the underlying mechanisms of TME-mediated therapy resistance can provide insights into developing novel therapeutic strategies to overcome these challenges.
TME shown to influence the delivery and distribution of anti-cancer drugs in tumors, affecting their efficacy. Strategies to modify the TME to improve drug delivery, such as using nanotechnology-based approaches or modulating the tumor vasculature, have shown promising results in preclinical and clinical studies. In addition to immune and stromal components, the role of the extracellular matrix (ECM) in the TME has gained increasing attention. ECM remodeling can impact tumor.
Study findings shows that the most promising approaches is the use of immunotherapy, which aims to enhance the immune system's ability to recognize and attack cancer cells. Immunotherapy drugs such as checkpoint inhibitors, chimeric antigen receptor (CAR) T cells, and immune-stimulatory monoclonal antibodies have been approved for the treatment of different cancer types. Another approach is the use of drugs that target the extracellular matrix components, such as hyaluronic acid and collagen, which can promote tumor growth and metastasis. These drugs can disrupt the physical barriers that prevent immune cells and therapeutic agents from reaching the tumor cells, enhancing their efficacy. Other novel therapeutic strategies targeting the TME include the use of nanoparticles, gene therapy, and the modulation of the gut microbiome. These approaches have shown promising results in preclinical studies and clinical trials.
Emerging evidence suggests that targeting the TME may be a promising therapeutic strategy for cancer treatment. For example, inhibiting specific signaling pathways involved in TME-mediated tumor growth and metastasis, or modulating the immune response in the TME, can lead to improved treatment outcomes. Recent research has identified novel targets within the TME that can be exploited for cancer therapy. For instance, targeting cancer-associated fibroblasts or immune checkpoint inhibitors have shown promising results in preclinical and clinical studies.
Despite the potential therapeutic implications of targeting the TME, there are challenges in developing effective strategies due to the complex and dynamic nature of the TME. Further research is needed to fully understand the TME and develop innovative therapeutic approaches for cancer treatment. Studies shows that, understanding the dynamic changes in the TME during cancer progression and treatment can help identify biomarkers for predicting treatment response and resistance. This can lead to personalized treatment approaches for patients with cancer.
Overall, unravelling the hidden impact of the tumour microenvironment has the potential to revolutionize cancer treatment by providing insights into novel therapeutic strategies that can improve patient outcomes and overcome treatment resistance. Further research in this area has the potential to uncover novel therapeutic strategies that can improve patient outcomes and overcome treatment resistance. Tumor microenvironment (TME) has been found to play a crucial role in cancer progression and treatment response. Studies have shown that the TME can influence tumor growth, angiogenesis, immune response, and drug resistance.
Tumor Microenvironment (TME) Composition in Tanzanian Cancer Patients: The study found that the TME in Tanzanian cancer patients is characterized by a high abundance of tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), which may contribute to immune evasion and tumor progression.
Challenges and Opportunities: The research highlighted challenges and opportunities in implementing novel therapeutic strategies for oncology in Tanzania, including limited access to advanced cancer treatments, infrastructure constraints, and socioeconomic factors. Addressing these challenges may be crucial in translating research findings into clinical practice and improving cancer care in Tanzania.

4. Discussion

The discussion of the research results emphasizes the critical role of the tumor microenvironment (TME) in cancer progression and treatment response. The TME, composed of various cell types and extracellular matrix components, can influence tumor growth, angiogenesis, immune response, and drug resistance through cross-talk between these different cell types.
Research has shown that the tumor microenvironment (TME) plays a critical role in cancer progression and treatment response. The complex interactions between tumor cells, immune cells, stromal cells, and extracellular matrix components in the TME contribute to tumor growth, angiogenesis, metastasis, and therapeutic resistance.
One significant impact of the TME is on the efficacy of conventional cancer therapies, including chemotherapy, radiation therapy, and immunotherapy. The presence of immune-suppressive cells and molecules in the TME can hinder the anti-tumor immune response and limit the effectiveness of immunotherapies. Understanding the underlying mechanisms of TME-mediated therapy resistance is crucial for developing novel therapeutic strategies to overcome these challenges.
Recent research has focused on targeting specific components of the TME as a potential therapeutic approach. For example, inhibiting the activity of immune-suppressive cells, such as regulatory T cells and myeloid-derived suppressor cells, or targeting the signaling pathways involved in tumor-stromal interactions, can enhance the anti-tumor immune response and improve treatment outcomes.
The research highlights the potential of targeting the TME as a promising therapeutic strategy for cancer treatment. Inhibiting specific signaling pathways involved in TME-mediated tumor growth and metastasis, or modulating the immune response in the TME, have shown promising results in preclinical and clinical studies.
The role of the extracellular matrix (ECM) in the TME has also gained increasing attention. ECM remodeling can impact tumor cell behavior, drug delivery, and treatment response. Strategies to modify the TME to improve drug delivery, such as using nanotechnology-based approaches or modulating the tumor vasculature, have shown promising results in preclinical and clinical studies.
Furthermore, TME heterogeneity and its dynamic changes during cancer progression and treatment response pose additional challenges. TME can evolve over time, leading to changes in tumor behavior, drug resistance, and immune response. Understanding the complex interplay between tumor cells and the TME during different stages of cancer can provide valuable insights for developing effective therapeutic strategies.
The research underscores the importance of unraveling the hidden impact of the tumor microenvironment in revolutionizing cancer treatment and improving patient outcomes by providing insights into novel therapeutic strategies that can overcome treatment resistance. Continued research in this area holds great promise for future cancer therapies, and further understanding and targeting of the TME can be a key strategy for advancing oncology treatments. Overall, further research in this area has the potential to uncover novel therapeutic strategies that can improve patient outcomes and overcome treatment resistance, and is crucial for advancing our understanding of the TME and developing effective therapies for oncology.
TME in cancer and emphasizes the critical role it plays in cancer progression and treatment response. The complex interactions between different cell types and extracellular matrix components within the TME can influence various aspects of tumor growth, angiogenesis, immune response, and drug resistance. Targeting the TME has emerged as a promising therapeutic strategy for cancer treatment.
Furthermore, understanding the dynamic changes in the TME during cancer progression and treatment can help identify biomarkers for predicting treatment response and resistance, leading to personalized treatment approaches. However, the complex and dynamic nature of the TME presents challenges in developing effective strategies, and further research is needed to fully understand the TME and develop innovative therapeutic approaches for cancer treatment.
The research suggests that inhibiting specific signaling pathways involved in TME-mediated tumor growth and metastasis, or modulating the immune response within the TME, can yield promising results in preclinical and clinical studies. Additionally, novel targets within the TME, such as cancer-associated fibroblasts or immune checkpoint inhibitors, have been identified as potential therapeutic options. Understanding the dynamic changes in the TME during cancer progression and treatment can also lead to the identification of biomarkers for predicting treatment response and resistance, enabling personalized treatment approaches.
However, developing effective strategies for targeting the TME presents challenges due to its complex and dynamic nature. Further research is needed to fully understand the TME and develop innovative therapeutic approaches for cancer treatment. Continued research in this area holds great promise for future cancer therapies and has the potential to uncover novel strategies for improving patient outcomes and overcoming treatment resistance.

In Tanzania Context

The findings of our research shed light on the complex interplay between the tumor microenvironment (TME) and cancer progression, treatment response, and therapeutic strategies in the context of Tanzania. Our research contributes to the growing body of evidence that highlights the crucial role of the TME in cancer pathogenesis and treatment outcomes, and underscores the need for novel therapeutic approaches to target the TME in the Tanzanian population.
Our research revealed that the TME is characterized by a complex network of cellular and non-cellular components, including stromal cells, immune cells, blood vessels, and extracellular matrix that actively contribute to tumor growth, angiogenesis, immune evasion, and drug resistance. These findings are consistent with studies conducted in other populations, which emphasize the universal relevance of the TME in cancer biology (Binnewies et al., 2018; Quail & Joyce, 2013).
Furthermore, our research demonstrated that the TME in Tanzania may contribute to the development of resistance to conventional cancer therapies, such as chemotherapy and targeted therapies. This may be attributed to the presence of specific immune cells, such as tumor-associated macrophages (TAMs) or regulatory T cells (Tregs), that impair anti-tumor immune responses and limit the efficacy of immunotherapies (Chen & Mellman, 2017). Our findings are in line with studies from other regions that have highlighted the role of the TME in modulating treatment response and resistance (Giraldo et al., 2019; Lu et al., 2017).
Our research also identified potential therapeutic targets within the TME that could be explored for novel therapeutic strategies in Tanzania. For instance, we found that targeting vascular endothelial growth factor (VEGF) or its receptors may be a promising approach to inhibit tumor angiogenesis and improve the efficacy of chemotherapy, consistent with findings from other studies in different populations (Ferrara et al., 2004; Jain et al., 2006; Zhao & Adjei, 2015). Additionally, immune checkpoint inhibitors, such as pembrolizumab and nivolumab, which block the PD-1/PD-L1 pathway, may hold promise in the Tanzanian population for enhancing anti-tumor immune responses, as demonstrated in other regions (Feng et al., 2019; Pardoll, 2012; Ribas & Wolchok, 2018).
Overall, our research underscores the significant impact of the TME on cancer progression, treatment response, and therapeutic strategies in Tanzania. The findings highlight the need for further research to elucidate the specific mechanisms underlying the TME in the Tanzanian context, and to identify additional potential therapeutic targets for the development of novel therapeutic strategies. These insights have the potential to inform clinical practice and contribute to improved patient outcomes in Tanzania and beyond.

5. Conclusion & Recomendation

The TME plays a critical role in cancer progression and treatment outcomes. The TME's complexity presents a significant challenge for developing effective therapeutic strategies, but recent advances in our understanding of the TME have led to the development of novel therapeutic approaches that target the microenvironment. Understanding the impact of the TME on cancer biology in Tanzania is critical for developing effective therapeutic strategies that target not only cancer cells but also the surrounding microenvironment. Targeting the TME is a promising approach for developing novel therapeutic strategies, and natural products may provide a cost-effective and accessible option for patients in Tanzania. These approaches include immunotherapy, targeting specific components of the TME, and inhibiting ECM degradation and angiogenesis. By unraveling the hidden impact of the tumor microenvironment, there is need to advance our understanding of cancer biology and pave the way for the development of innovative and effective therapeutic approaches for oncology. Further research is needed to fully understand the TME's role in cancer biology and to develop effective therapies that target this complex and dynamic environment.

Author Contributions

All the authors contributed to the conception, drafting and final revision of the manuscript.

Conflicts of Interest

The authors declare no competing interests.

Ethical Considerations

The study was conducted in accordance with the principles of the Declaration of Helsinki and relevant ethical guidelines. Ethical approval obtained from CREC before the commencement of the study.

Consent for publication

All authors read and approved the manuscript.

Abbreviations

TEM- Tumor Microenvironment; TAMs-tumor-associated macrophages.

References

  1. Baghban, R., Roshangar, L., Jahanban-Esfahlan, R., Seidi, K., Ebrahimi-Kalan, A., Jaymand, M., Kolahian, S., Javaheri, T., & Zare, P. (2020). Tumor microenvironment complexity and therapeutic implications at a glance. Cell Communication and Signaling, 18(1), 59. [CrossRef]
  2. Biancur, D. E., Kapner, K. S., Yamamoto, K., Banh, R. S., Neggers, J. E., Sohn, A. S. W., Wu, W., Manguso, R. T., Brown, A., Root, D. E., Aguirre, A. J., & Kimmelman, A. C. (2021). Functional Genomics Identifies Metabolic Vulnerabilities in Pancreatic Cancer. Cell Metabolism, 33(1), 199-210.e8. [CrossRef]
  3. Binnewies, M., Roberts, E. W., Kersten, K., Chan, V., Fearon, D. F., Merad, M., Coussens, L. M., Gabrilovich, D. I., Ostrand-Rosenberg, S., Hedrick, C. C., Vonderheide, R. H., Pittet, M. J., Jain, R. K., Zou, W., Howcroft, T. K., Woodhouse, E. C., Weinberg, R. A., & Krummel, M. F. (2018). Understanding the tumor immune microenvironment (TIME) for effective therapy. Nature Medicine, 24(5), 541–550. [CrossRef]
  4. Bray, F., Ferlay, J., Soerjomataram, I., Siegel, R. L., Torre, L. A., & Jemal, A. (2018). Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal for Clinicians, 68(6), 394–424. [CrossRef]
  5. Chen, D. S., & Mellman, I. (2017). Elements of cancer immunity and the cancer-immune set point. Nature, 541(7637), 321–330. [CrossRef]
  6. Egeblad, M., Nakasone, E. S., & Werb, Z. (2010). Tumors as organs: Complex tissues that interface with the entire organism. Developmental Cell, 18(6), 884–901. [CrossRef]
  7. Feng, X., Xu, W., Li, Z., Song, W., Ding, J., & Chen, X. (2019). Immunomodulatory Nanosystems. Advanced Science, 6(17), 1900101. [CrossRef]
  8. Ferrara, N., Hillan, K. J., Gerber, H.-P., & Novotny, W. (2004). Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nature Reviews. Drug Discovery, 3(5), 391–400. [CrossRef]
  9. Giraldo, N. A., Sanchez-Salas, R., Peske, J. D., Vano, Y., Becht, E., Petitprez, F., Validire, P., Ingels, A., Cathelineau, X., Fridman, W. H., & Sautès-Fridman, C. (2019). The clinical role of the TME in solid cancer. British Journal of Cancer, 120(1), Article 1. [CrossRef]
  10. Hanahan, D., & Coussens, L. M. (2012). Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell, 21(3), 309–322. [CrossRef]
  11. Hegde, M., Mukherjee, M., Grada, Z., Pignata, A., Landi, D., Navai, S. A., Wakefield, A., Fousek, K., Bielamowicz, K., Chow, K. K. H., Brawley, V. S., Byrd, T. T., Krebs, S., Gottschalk, S., Wels, W. S., Baker, M. L., Dotti, G., Mamonkin, M., Brenner, M. K., … Ahmed, N. (2016). Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. The Journal of Clinical Investigation, 126(8), 3036–3052. [CrossRef]
  12. Hegde, P. S., Karanikas, V., & Evers, S. (2016). The Where, the When, and the How of Immune Monitoring for Cancer Immunotherapies in the Era of Checkpoint Inhibition. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 22(8), 1865–1874. [CrossRef]
  13. Jain, L., Venitz, J., & Figg, W. D. (2006). Randomized discontinuation trial of sorafenib (BAY 43-9006). Cancer Biology & Therapy, 5(10), 1270–1272. [CrossRef]
  14. Joyce, J. A., & Fearon, D. T. (2015). T cell exclusion, immune privilege, and the tumor microenvironment. Science (New York, N.Y.), 348(6230), 74–80. [CrossRef]
  15. Kanz, B. A., Pollack, M. H., Johnpulle, R., Puzanov, I., Horn, L., Morgans, A., Sosman, J. A., Rapisuwon, S., Conry, R. M., Eroglu, Z., & Johnson, D. B. (2016). Safety and efficacy of anti-PD-1 in patients with baseline cardiac, renal, or hepatic dysfunction. Journal for Immunotherapy of Cancer, 4, 60. [CrossRef]
  16. Khalaf, K., Hana, D., Chou, J. T.-T., Singh, C., Mackiewicz, A., & Kaczmarek, M. (2021). Aspects of the Tumor Microenvironment Involved in Immune Resistance and Drug Resistance. Frontiers in Immunology, 12, 656364. [CrossRef]
  17. Khalil, A. A., & Friedl, P. (2010). Determinants of leader cells in collective cell migration. Integrative Biology: Quantitative Biosciences from Nano to Macro, 2(11–12), 568–574. [CrossRef]
  18. Klemm, F., & Joyce, J. A. (2015). Microenvironmental regulation of therapeutic response in cancer. Trends in Cell Biology, 25(4), 198–213. [CrossRef]
  19. Kutoka, P. T., Seidu, T. A., Baye, V., Khamis, A. M., Omonova, C. T. qizi, & Wang, B. (2022). Insights into Tumor Microenvironment (TME) and the Nano Approaches to Suppress Tumor Growth. OpenNano, 7, 100041. [CrossRef]
  20. Lu, H., Chen, I., Shimoda, L. A., Park, Y., Zhang, C., Tran, L., Zhang, H., & Semenza, G. L. (2017). Chemotherapy-Induced Ca2+ Release Stimulates Breast Cancer Stem Cell Enrichment. Cell Reports, 18(8), 1946–1957. [CrossRef]
  21. Pardoll, D. M. (2012). The blockade of immune checkpoints in cancer immunotherapy. Nature Reviews. Cancer, 12(4), 252–264. [CrossRef]
  22. Pernot, S., Evrard, S., & Khatib, A.-M. (2022). The Give-and-Take Interaction Between the Tumor Microenvironment and Immune Cells Regulating Tumor Progression and Repression. Frontiers in Immunology, 13. https://www.frontiersin.org/articles/10.3389/fimmu.2022.850856.
  23. Pucci, C., Martinelli, C., & Ciofani, G. (2019). Innovative approaches for cancer treatment: Current perspectives and new challenges. Ecancermedicalscience, 13, 961. [CrossRef]
  24. Quail, D. F., & Joyce, J. A. (2013). Microenvironmental regulation of tumor progression and metastasis. Nature Medicine, 19(11), 1423–1437. [CrossRef]
  25. Quail, D. F., & Joyce, J. A. (2017). The Microenvironmental Landscape of Brain Tumors. Cancer Cell, 31(3), 326–341. [CrossRef]
  26. Ribas, A., & Wolchok, J. D. (2018). Cancer immunotherapy using checkpoint blockade. Science (New York, N.Y.), 359(6382), 1350–1355. [CrossRef]
  27. Runa, F., Hamalian, S., Meade, K., Shisgal, P., Gray, P., & Kelber, J. (2017). Tumor microenvironment heterogeneity: Challenges and opportunities. Current Molecular Biology Reports, 3(4), 218–229. [CrossRef]
  28. Sharma, P., Hu-Lieskovan, S., Wargo, J. A., & Ribas, A. (2017). Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell, 168(4), 707–723. [CrossRef]
  29. Sounni, N. E., Cimino, J., Blacher, S., Primac, I., Truong, A., Mazzucchelli, G., Paye, A., Calligaris, D., Debois, D., De Tullio, P., Mari, B., De Pauw, E., & Noel, A. (2014). Blocking Lipid Synthesis Overcomes Tumor Regrowth and Metastasis after Antiangiogenic Therapy Withdrawal. Cell Metabolism, 20(2), 280–294. [CrossRef]
  30. Sounni, N. E., & Noel, A. (2013). Targeting the tumor microenvironment for cancer therapy. Clinical Chemistry, 59(1), 85–93. [CrossRef]
  31. Tauriello, D. V. F., Palomo-Ponce, S., Stork, D., Berenguer-Llergo, A., Badia-Ramentol, J., Iglesias, M., Sevillano, M., Ibiza, S., Cañellas, A., Hernando-Momblona, X., Byrom, D., Matarin, J. A., Calon, A., Rivas, E. I., Nebreda, A. R., Riera, A., Attolini, C. S.-O., & Batlle, E. (2018). TGFβ drives immune evasion in genetically reconstituted colon cancer metastasis. Nature, 554(7693), 538–543. [CrossRef]
  32. Wang, M., Zhao, J., Zhang, L., Wei, F., Lian, Y., Wu, Y., Gong, Z., Zhang, S., Zhou, J., Cao, K., Li, X., Xiong, W., Li, G., Zeng, Z., & Guo, C. (2017). Role of tumor microenvironment in tumorigenesis. Journal of Cancer, 8(5), 761–773. [CrossRef]
  33. Zhao, Y., & Adjei, A. A. (2015). Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor. The Oncologist, 20(6), 660–673. [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Copyright: This open access article is published under a Creative Commons CC BY 4.0 license, which permit the free download, distribution, and reuse, provided that the author and preprint are cited in any reuse.
Prerpints.org logo

Preprints.org is a free preprint server supported by MDPI in Basel, Switzerland.

facebook logotwitter logolinkedin logo
MDPI Initiatives
Important Links
Subscribe

Disclaimer

Terms of Use

Privacy Policy

© 2024 MDPI (Basel, Switzerland) unless otherwise stated