Tumor Microenvironment and Its Role in Modulating Anti-Tumor Immune Responses: A Comprehensive Review
DOI:
https://doi.org/10.64229/p3cwkg42Keywords:
Tumor microenvironment, Immune modulation, Cancer immunotherapy, Tumor-mmune interactions, Translational oncologyAbstract
The tumor microenvironment (TME) is a highly dynamic and heterogeneous ecosystem composed of malignant cells, immune infiltrates, stromal elements, vascular networks, and extracellular matrix components that collectively shape tumor progression and therapeutic response. Accumulating evidence demonstrates that the TME plays a decisive role in modulating anti-tumor immunity by fostering immune suppression, metabolic stress, and physical barriers that limit immune cell infiltration and function. This review provides a comprehensive overview of the cellular, molecular, metabolic, and epigenetic features of the TME that govern immune evasion and resistance to immunotherapy. We discuss the functional roles of key immune and stromal populations, including tumor-associated macrophages, myeloid-derived suppressor cells, regulatory T cells, cancer-associated fibroblasts, and endothelial cells, highlighting their contribution to immunosuppressive signaling networks. Furthermore, we examine how hypoxia, nutrient competition, immune checkpoint expression, and extracellular matrix remodeling impair effective anti-tumor immune responses. The review also summarizes current and emerging therapeutic strategies aimed at reprogramming the TME, including immune checkpoint blockade combinations, metabolic and epigenetic modulation, stromal targeting, and nanotechnology-based delivery systems. Finally, we highlight advances in single-cell, spatial, and multi-omics technologies that are transforming TME profiling and enabling precision immuno-oncology. A deeper understanding of TME-driven immune regulation is essential for overcoming therapeutic resistance and improving durable clinical outcomes in cancer patients.
References
[1]Kim SK, Cho SW. The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment. Frontiers in Pharmacology, 2022, 13, 868695. DOI: 10.3389/fphar.2022.868695
[2]Augustin RC, Delgoffe GM, Najjar YG. Characteristics of the tumor microenvironment that influence immune cell functions: hypoxia, oxidative stress, metabolic alterations. Cancers, 2020,12(12), 3802. DOI: 10.3390/cancers12123802
[3]Senthebane DA, Rowe A, Thomford NE, Shipanga H, Munro D, Al Mazeedi MAM, et al. The role of tumor microenvironment in chemoresistance: to survive, keep your enemies closer. International Journal of Molecular Sciences, 2017, 18, 1586. DOI: 10.3390/ijms18071586
[4]Jia QZ, Wang A, Yuan YX, Zhu B, Long HX. Heterogeneity of the tumor immune microenvironment and its clinical relevance. Experimental Hematology & Oncology, 2022, 11(1), 24. DOI: 10.1186/s40164-022-00277-y
[5]Petitprez F, Meylan M, de Reyniès A, Sautès-Fridman C, Fridman WH. The tumor microenvironment in the response to immune checkpoint blockade therapies. Frontiers in Immunology, 2020, 11, 784. DOI: 10.3389/fimmu.2020.00784
[6]Hu X, Ren J, Xue QF, Luan RM, Ding DY, Tan J, et al. Anti-PD-1/PD-L1 and anti-CTLA-4 associated checkpoint inhibitor pneumonitis in non-small cell lung cancer: Occurrence, pathogenesis and risk factors. International Journal of Oncology, 2023, 63(5), 122. DOI: 10.3892/ijo.2023.5570
[7]Shee K, Yang W, Hinds JW, Hampsch RA, Varn FS, Traphagen NA, et al. Therapeutically targeting tumor microenvironment-mediated drug resistance in estrogen receptor-positive breast cancer. The Journal of Experimental Medicine, 2018, 215(3), 895-910. DOI: 10.1084/jem.20171818
[8]Nagorsen D, Voigt S, Berg E, Stein H, Thiel E, Loddenkemper C. Tumor-infiltrating macrophages and dendritic cells in human colorectal cancer: relation to local regulatory T cells, systemic T-cell response against tumor-associated antigens and survival. Journal of Translational Medicine, 2007, 5, 62. DOI: 10.1186/1479-5876-5-62
[9]Wang SJ, Wang JR, Chen ZQ, Luo JM, Guo W, Sun LL, et al. Targeting M2-like tumor-associated macrophages is a potential therapeutic approach to overcome antitumor drug resistance. NPJ Precision Oncology, 2024, 8(1), 31. DOI: 10.1038/s41698-024-00522-z
[10]Bilotta MT, Antignani A, Fitzgerald DJ. Managing the TME to improve the efficacy of cancer therapy. Frontiers in Immunology, 2022, 13, 954992. DOI: 10.3389/fimmu.2022.954992
[11]Munn DH, Bronte V. Immune suppressive mechanisms in the tumor microenvironment. Current Opinion Immunology, 2016, 39, 1-6. DOI: 10.1016/j.coi.2015.10.009
[12]Han ZY, Dong YC, Lu JZ, Yang F, Zheng YC, Yang HY. Role of hypoxia in inhibiting dendritic cells by VEGF signaling in tumor microenvironments: mechanism and application. American Journal of Cancer Research, 2021, 11(8), 3777-3793.
[13]Khosravi G, Mostafavi S, Bastan S, Ebrahimi N, Gharibvand RS, Eskandari N. Immunologic tumor microenvironment modulators for turning cold tumors hot. Cancer Communications, 2024, 44, 521-553. DOI: 10.1002/cac2.12539
[14]Zhu DQ, Zeng SY, Su C, Li JJ, Xuan YW, Lin YK, et al. The interaction between DNA methylation and tumor immune microenvironment: from the laboratory to clinical applications. Clinical Epigenetics, 2024, 16(1), 24. DOI: 10.1186/s13148-024-01633-x
[15]Poli V, Fagnocchi L, Zippo A. Tumorigenic cell reprogramming and cancer plasticity: Interplay between signaling, microenvironment, and epigenetics. Stem Cells International, 2018, 2018, 4598195. DOI: 10.1155/2018/4598195
[16]Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends in Genetics, 2009, 25(1), 30-38. DOI: 10.1016/j.tig.2008.10.012
[17]Franco PIR, Rodrigues AP, de Menezes LB, Miguel MP. Tumor microenvironment components: Allies of cancer progression. Pathology-Research and Practice, 2020, 216(1), 152729. DOI: 10.1016/j.prp.2019.152729
[18]Ahluwalia P, Ahluwalia M, Mondal AK, Sahajpal NS, Kota V, Rojiani MV, et al. Natural killer cells and dendritic cells: Expanding clinical relevance in the non-small cell lung cancer (NSCLC) tumor microenvironment. Cancers, 2021, 13(16), 4037. DOI: 10.3390/cancers13164037
[19]Ali A, Ali SL, Ullah W, Khan A. Gene expression profiling identifies CAV1, CD44, and TFRC as potential diagnostic markers and therapeutic targets for multiple myeloma. Cell Biochemistry and Biophysics, 2025, 83(3), 3633-3650. DOI: 10.1007/s12013-025-01743-0
[20]Yang L, Pang Y, Moses HL. TGF-β and immune cells: an important regulatory axis in the tumor microenvironment and progression. Trends in Immunology, 2010, 31(6), 220–227. DOI: 10.1016/j.it.2010.04.002
[21]Huang Y, Chen ZJ, Shen G, Fang SG, Zheng JJ, Chi ZP, et al. Immune regulation and the tumor microenvironment in anti-PD-1/PDL-1 and anti-CTLA-4 therapies for cancer immune evasion: A bibliometric analysis. Human Vaccines & Immunotherapeutics, 2024, 20(1), 2318815. DOI: 10.1080/21645515.2024.2318815
[22]Goswami KK, Ghosh T, Ghosh S, Sarkar M, Bose A, Baral R. Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cellular Immunology, 2017, 316, 1-10. DOI: 10.1016/j.cellimm.2017.04.005
[23]Kumar V, Gabrilovich DI. Hypoxia‐inducible factors in regulation of immune responses in tumour microenvironment. Immunology, 2014, 143(4), 512-519. DOI: 10.1111/imm.12380
[24]Suzuki HI, Katsura A, Matsuyama H, Miyazono K. MicroRNA regulons in tumor microenvironment. Oncogene, 2015, 34(24), 3085-3094. DOI: 10.1038/onc.2014.254
[25]Ali A, Ali SL, Alamri A, Khatrawi EM, Baiduissenova A, Suleimenova F, et al. Multi-epitope-based vaccine models prioritization against Astrovirus MLB1 using immunoinformatics and reverse vaccinology approaches. Journal of Genetic Engineering and Biotechnology, 2025, 23(1), 100451. DOI: 10.1016/j.jgeb.2024.100451
[26]Ali A, Ali SL, Alamri A, Khatrawi EM, Baiduissenova A, Suleimenova F, et al. Multi-epitope-based vaccine models prioritization against Astrovirus MLB1 using immunoinformatics and reverse vaccinology approaches. Journal of Genetic Engineering and Biotechnology, 2025, 23(1), 100451. DOI: 10.1016/j.jgeb.2024.100451
[27]Mirlekar B. Tumor promoting roles of IL-10, TGF-β, IL-4, and IL-35: Its implications in cancer immunotherapy. SAGE Open Medicine, 2022, 10:20503121211069012. DOI: 10.1177/20503121211069012
[28]Zhuang L, Zhao YL, Yang L, Li LS, Ye ZY, Ali A, et al. Harnessing bioinformatics for the development of a promising multi-epitope vaccine against tuberculosis: The ZL9810L vaccine. Decoding Infection and Transmission, 2024, 2, 100026. DOI: 10.1016/j.dcit.2024.100026
[29]Bauer M, Jasinski-Bergner S, Mandelboim O, Wickenhauser C, Seliger B. Epstein-Barr virus-associated malignancies and immune escape: the role of the tumor microenvironment and tumor cell evasion strategies. Cancers, 2021, 13(20), 5189. DOI: 10.3390/cancers13205189
[30]Zhuang L, Ali A, Yang L, Ye ZY, Li LS, Ni RZ, et al. Leveraging computer-aided design and artificial intelligence to develop a next-generation multi-epitope tuberculosis vaccine candidate. Infectious Medicine, 2024, 3(4), 100148. DOI: 10.1016/j.imj.2024.100148
[31]Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. Journal of Cellular Physiology, 2019, 234(6), 8509-8521. DOI: 10.1002/jcp.27782
[32]Vivier E, Rebuffet L, Narni-Mancinelli E, Cornen S, Igarashi RY, Fantin VR. Natural killer cell therapies. Nature, 2024, 626, 727-736. DOI: 10.1038/s41586-023-06945-1
[33]Schraml BU, e Sousa CR. Defining dendritic cells. Current Opinion in Immunology, 2015, 32, 13-20. DOI: 10.1016/j.coi.2014.11.001
[34]Goswami TK, Singh M, Dhawan M, Mitra S, Emran T Bin, Rabaan AA, et al. Regulatory T cells (Tregs) and their therapeutic potential against autoimmune disorders-Advances and challenges. Human Vaccines & Immunotherapeutics, 2022, 18(1), 2035117. DOI: 10.1080/21645515.2022.2035117
[35]Umansky V, Blattner C, Gebhardt C, Utikal J. The role of myeloid-derived suppressor cells (MDSC) in cancer progression. Vaccines, 2016, 4(4), 36. DOI: 10.3390/vaccines4040036
[36]Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. Journal of Hematology & Oncology, 2017, 10, 58. DOI: 10.1186/s13045-017-0430-2
[37]Wu PJ, Gao W, Su M, Nice EC, Zhang WH, Lin J, et al. Adaptive mechanisms of tumor therapy resistance driven by tumor microenvironment. Frontiers in Cell and Developmental Biology, 2021, 9, 641469. DOI: 10.3389/fcell.2021.641469
[38]Ali A, Manzoor U, Ali SL, Nousheen R, Ullah W, Adil K. Analysis of the capability of IgG antibodies and receptors with their relationships to food tolerance and autoimmune disorders. International Journal of Natural Medicine and Health Sciences, 2023, 3(1), 25-32. DOI: 10.52461/ijnms.v3i1.2455
[39]Song E, Chow RD. Mutations in IFN-γ signaling genes sensitize tumors to immune checkpoint blockade. Cancer Cell, 2023, 41(4), 651-652. DOI: 10.1016/j.ccell.2023.02.013
[40]Qian JW, Wang C, Wang B, Yang J, Wang YD, Luo FF, et al. The IFN-γ/PD-L1 axis between T cells and tumor microenvironment: hints for glioma anti-PD-1/PD-L1 therapy. Journal of Neuroinflammation, 2018, 15(1), 290. DOI: 10.1186/s12974-018-1330-2
[41]Ali A, Manzoor U, Ali SL, Marsool MD, Parida PK, Marsool AD, et al. Currently trending and futuristic biological modalities in the management of different types of diabetes: A comprehensive review. Journal of Population Therapeutics & Clinical Pharmacology, 2023, 30(18), 2948-2970. DOI: 10.53555/jptcp.v30i18.3467
[42]Ali SL, Ali A, Alamri A, Baiduissenova A, Dusmagambetov M, Abduldayeva A. Genomic annotation for vaccine target identification and immunoinformatics-guided multi-epitope-based vaccine design against Songling virus through screening its whole genome encoded proteins. Frontiers in Immunology, 2023, 14, 1284366. DOI: 10.3389/fimmu.2023.1284366
[43]Barnestein R, Galland L, Kalfeist L, Ghiringhelli F, Ladoire S, Limagne E. Immunosuppressive tumor microenvironment modulation by chemotherapies and targeted therapies to enhance immunotherapy effectiveness. Oncoimmunology, 2022, 11(1), 2120676. DOI: 10.1080/2162402X.2022.2120676
[44]Manzoor U, Ali A, Ali SL, Abdelkarem O, Kanwal S, Alotaibi SS, et al. Mutational screening of GDAP1 in dysphonia associated with Charcot-Marie-Tooth disease: clinical insights and phenotypic effects. Journal of Genetic Engineering and Biotechnology, 2023, 21(1), 119. DOI: 10.1186/s43141-023-00568-9
[45]Aiman S, Ahmad A, Khan AA, Alanazi AM, Samad A, Ali SL, et al. Vaccinomics-based next-generation multi-epitope chimeric vaccine models prediction against Leishmania tropica-A hierarchical subtractive proteomics and immunoinformatics approach. Froniers in Immunology, 2023, 14, 1259612. DOI: 10.3389/fimmu.2023.1259612
[46]Qiao Y, Wei LY, Su YJ, Tan QY, Yang XC, Li SX. Nanoparticle-Based Strategies to Enhance the Efficacy of STING Activators in Cancer Immunotherapy. International Journal of Nanomedicine, 2025, 20, 5429-5456. DOI: 10.2147/IJN.S515893
[47]Lin YX, Xu JX, Lan HY. Tumor-associated macrophages in tumor metastasis: biological roles and clinical therapeutic applications. Journal of Hematology Oncology, 2019, 12(1), 76. DOI: 10.1186/s13045-019-0760-3
[48]Gabrilovich DI. Myeloid-derived suppressor cells. Cancer Immunol Research, 2017, 5(1), 3-8. DOI: 10.1158/2326-6066.CIR-16-0297
[49]Sakaguchi S, Mikami N, Wing JB, Tanaka A, Ichiyama K, Ohkura N. Regulatory T cells and human disease. Annual Review of Immunology, 2020, 38, 541-566. DOI: 10.1146/annurev-immunol-042718-041717
[50]Maglie R, Solimani F, Didona D, Pipitò C, Antiga E, Di Zenzo G. The cytokine milieu of bullous pemphigoid: Current and novel therapeutic targets. Frontiers in Medicine, 2023, 10, 1128154. DOI: 10.3389/fmed.2023.1128154
[51]Kaur J, Reinhardt DP. Extracellular matrix (ECM) molecules. Stem Cell Biology and Tissue Engineering in Dental Sciences, 2015, 25-45. DOI: 10.1016/B978-0-12-397157-9.00003-5
[52]Zhang H, Yue XH, Chen Z, Liu C, Wu WT, Zhang N, et al. Define cancer-associated fibroblasts (CAFs) in the tumor microenvironment: new opportunities in cancer immunotherapy and advances in clinical trials. Molecular Cancer, 2023, 22(1), 159. DOI: 10.1186/s12943-023-01860-5
[53]Lanitis E, Irving M, Coukos G. Targeting the tumor vasculature to enhance T cell activity. Current Opinion in Immunology, 2015, 33, 55-63. DOI: 10.1016/j.coi.2015.01.011
[54]Lau AN, Vander Heiden MG. Metabolism in the tumor microenvironment. Annual Review of Cancer Biology, 2020, 4, 17-40. DOI: 10.1146/annurev-cancerbio-030419-033333
[55]Niemann J, Kühnel F. Oncolytic viruses: adenoviruses. Virus Genes, 2017, 53, 700-706. DOI: 10.1007/s11262-017-1488-1
[56]Yang ZG, Ma YF, Zhao H, Yuan Y, Kim BYS. Nanotechnology platforms for cancer immunotherapy. Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology, 2020, 12(2), e1590. DOI: 10.1002/wnan.1590
[57]van Dam S, Baars MJD, Vercoulen Y. Multiplex tissue imaging: spatial revelations in the tumor microenvironment. Cancers, 2022, 14(13), 3170. DOI: 10.3390/cancers14133170
[58]Lee HW, Chung W, Lee H-O, Jeong DE, Jo A, Lim JE, et al. Single-cell RNA sequencing reveals the tumor microenvironment and facilitates strategic choices to circumvent treatment failure in a chemorefractory bladder cancer patient. Genome Medicine, 2020, 12(1),1-21. DOI: 10.1186/s13073-020-00741-6
[59]Wang N, Li X, Wang RS, Ding ZY. Spatial transcriptomics and proteomics technologies for deconvoluting the tumor microenvironment. Biotechnology Journal, 2021, 16(9), 2100041. DOI: 10.1002/biot.202100041
[60]Villasboas B JC, Ansell S. Heterogeneity of the Tumor Microenvirontment in diffuse large B-Cell lymphoma revealed by deep phenotyping using Mass Cytometry (CyTOF). American Society of Hematology, 2016, 128(22), 2941. DOI: 10.1182/blood.V128.22.2941.2941
[61]Gu ZR, Wu QY, Shang BQ, Zhang KT, Zhang W. Organoid co‐culture models of the tumor microenvironment promote precision medicine. Cancer Innovation, 2024, 3(1), e101. DOI: 10.1002/cai2.101
[62]Galli F, Aguilera JV, Palermo B, Markovic SN, Nisticò P, Signore A. Relevance of immune cell and tumor microenvironment imaging in the new era of immunotherapy. Journal of Experimental & Clinical Cancer Research, 2020, 39(1), 89. DOI: 10.1186/s13046-020-01586-y
[63]Liu CC, Steen CB, Newman AM. Computational approaches for characterizing the tumor immune microenvironment. Immunology, 2019, 158(2), 70-84. DOI: 10.1111/imm.13101
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