The immune system constitutes a highly coordinated network of cellular and molecular components that protect the host from infection, tissue injury, and malignant transformation. Immune cells, encompassing innate and adaptive lineages, serve as core effectors of this system. Innate immune cells, including macrophages, DCs, and NK cells, initiate rapid, nonspecific responses while shaping subsequent adaptive immunity. Adaptive immune cells, primarily T lymphocytes and B lymphocytes, mediate antigen-specific responses and long-term immunological memory. Within the tumor microenvironment (TME), these populations exhibit context-dependent functions, with cytotoxic subsets exerting tumor control and regulatory subsets facilitating immune evasion. TAMs, Tregs, and MDSCs exemplify immunosuppressive mechanisms, whereas cytotoxic CD8⁺ T cells, NK cells, and DCs drive anti-tumor immunity. Cancer immunotherapy has harnessed these mechanisms, employing immune checkpoint inhibitors targeting PD-1, PD-L1, or CTLA-4, adoptive cell therapies such as chimeric antigen receptor T cell (CAR-T) therapy and tumor-infiltrating lymphocyte (TIL) therapy, as well as therapeutic cancer vaccines. Advances in single-cell RNA sequencing and spatial transcriptomics have revealed extensive cellular heterogeneity and spatial organization within the TME, uncovering mechanisms of immune suppression and therapeutic resistance. Integrating these high-dimensional approaches with rationally designed combination therapies provides a framework for personalized immunotherapy. This review presents a comprehensive overview of immune cell roles in tumor progression, immune evasion, and therapeutic intervention, highlighting strategies to exploit the immune landscape for durable clinical benefit.
1. Paludan SR, Pradeu T, Masters SL, Mogensen TH. Constitutive immune mechanisms: mediators of host defence and immune regulation. Nature Reviews Immunology. 2021;21(3):137-50.
2. McDonald DR, Levy O. Innate immunity. Clinical immunology: Elsevier; 2019. p. 39-53. e1.
3. Ghasemi M, Abbasi L, Ghanbari Naeini L, Kokabian P, Nameh Goshay Fard N, Givtaj N. Dendritic cells and natural killer cells: The road to a successful oncolytic virotherapy. Frontiers in Immunology. 2023;13:950079.
4. Kavathas PB, Krause PJ, Ruddle NH. Adaptive immunity: antigen recognition by T and B lymphocytes. Immunoepidemiology: Springer; 2019. p. 55-74.
5. Biram A, Davidzohn N, Shulman Z. T cell interactions with B cells during germinal center formation, a three‐step model. Immunological reviews. 2019;288(1):37-48.
6. Kim SK, Cho SW. The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment. Frontiers in pharmacology. 2022;13:868695.
7. Wang H, Tian T, Zhang J. Tumor-associated macrophages (TAMs) in colorectal cancer (CRC): from mechanism to therapy and prognosis. International journal of molecular sciences. 2021;22(16):8470.
8. Lakshmanachetty S, Cruz-Cruz J, Hoffmeyer E, Cole AP, Mitra SS. New insights into the multifaceted role of myeloid-derived suppressor cells (MDSCs) in high-grade gliomas: from metabolic reprograming, immunosuppression, and therapeutic resistance to current strategies for targeting MDSCs. Cells. 2021;10(4):893.
9. Pathania AS, Prathipati P, Olwenyi OA, Chava S, Smith OV, Gupta SC, et al. miR-15a and miR-15b modulate natural killer and CD8+ T-cell activation and anti-tumor immune response by targeting PD-L1 in neuroblastoma. Molecular Therapy-Oncolytics. 2022;25:308-29.
10. Qasim W. Allogeneic CAR T cell therapies for leukemia. American journal of hematology. 2019;94(S1):S50-S4.
11. Cheng X, Peng T, Chu T, Yang Y, Liu J, Gao Q, et al. Application of single-cell and spatial omics in deciphering cellular hallmarks of cancer drug response and resistance. Journal of Hematology & Oncology. 2025;18:70.
12. Kanneganti T-D. Intracellular innate immune receptors: Life inside the cell. Immunological reviews. 2020;297(1):5.
13. Kwon DH, Lee H, Park C, Hong S-H, Hong SH, Kim G-Y, et al. Glutathione induced immune-stimulatory activity by promoting M1-like macrophages polarization via potential ROS scavenging capacity. Antioxidants. 2019;8(9):413.
14. Liu R, Li J, Liu L, Wang W, Jia J. Tumor-associated macrophages (TAMs): Constructing an immunosuppressive microenvironment bridge for pancreatic ductal adenocarcinoma (PDAC)☆. Cancer Pathogenesis and Therapy. 2025;3(03):183-96.
15. Wang H, Yung MM, Ngan HY, Chan KK, Chan DW. The impact of the tumor microenvironment on macrophage polarization in cancer metastatic progression. International journal of molecular sciences. 2021;22(12):6560.
16. Del Prete A, Salvi V, Soriani A, Laffranchi M, Sozio F, Bosisio D, et al. Dendritic cell subsets in cancer immunity and tumor antigen sensing. Cellular & molecular immunology. 2023;20(5):432-47.
17. Piñeiro Fernández J, Luddy KA, Harmon C, O’Farrelly C. Hepatic tumor microenvironments and effects on NK cell phenotype and function. International journal of molecular sciences. 2019;20(17):4131.
18. Masucci MT, Minopoli M, Carriero MV. Tumor associated neutrophils. Their role in tumorigenesis, metastasis, prognosis and therapy. Frontiers in oncology. 2019;9:1146.
19. De Cicco P, Ercolano G, Ianaro A. The new era of cancer immunotherapy: targeting myeloid-derived suppressor cells to overcome immune evasion. Frontiers in immunology. 2020;11:1680.
20. Ge Z, Ding S. The crosstalk between tumor-associated macrophages (TAMs) and tumor cells and the corresponding targeted therapy. Frontiers in oncology. 2020;10:590941.
21. Abdollahi E, Johnston TP, Ghaneifar Z, Vahedi P, Goleij P, Azhdari S, et al. Immunomodulatory therapeutic effects of curcumin on M1/M2 macrophage polarization in inflammatory diseases. Current molecular pharmacology. 2023;16(1):2-14.
22. Tang Y, Shi T, Lin S, Fang T. Current status of research on the mechanisms of tumor-associated macrophages in esophageal cancer progression. Frontiers in Oncology. 2024;14:1450603.
23. Shi J, Xiao W, Liu Y, Fu X, Peng M. Tumor-associated macrophages and platelets in tumor microenvironment and its potential therapeutic role in ovarian cancer. Clinical and Translational Oncology. 2025:1-13.
24. Bhattacharya S, Aggarwal A. M2 macrophages and their role in rheumatic diseases. Rheumatology international. 2019;39(5):769-80.
25. Zeng D, Ye Z, Wu J, Zhou R, Fan X, Wang G, et al. Macrophage correlates with immunophenotype and predicts anti-PD-L1 response of urothelial cancer. Theranostics. 2020;10(15):7002.
26. Liang Y, He J, Chen X, Yin L, Yuan Q, Zeng Q, et al. The emerging roles of metabolism in the crosstalk between breast cancer cells and tumor-associated macrophages. International journal of biological sciences. 2023;19(15):4915.
27. Larionova I, Tuguzbaeva G, Ponomaryova A, Stakheyeva M, Cherdyntseva N, Pavlov V, et al. Tumor-associated macrophages in human breast, colorectal, lung, ovarian and prostate cancers. Frontiers in oncology. 2020;10:566511.
28. Qian Y, Yin Y, Zheng X, Liu Z, Wang X. Metabolic regulation of tumor-associated macrophage heterogeneity: insights into the tumor microenvironment and immunotherapeutic opportunities. Biomarker research. 2024;12(1):1.
29. Peng X, He Y, Huang J, Tao Y, Liu S. Metabolism of dendritic cells in tumor microenvironment: for immunotherapy. Frontiers in immunology. 2021;12:613492.
30. Lurje I, Hammerich L, Tacke F. Dendritic cell and T cell crosstalk in liver fibrogenesis and hepatocarcinogenesis: implications for prevention and therapy of liver cancer. International journal of molecular sciences. 2020;21(19):7378.
31. Matsuo K, Yoshie O, Kitahata K, Kamei M, Hara Y, Nakayama T. Recent progress in dendritic cell-based cancer immunotherapy. Cancers. 2021;13(10):2495.
32. Hubert M, Gobbini E, Couillault C, Manh T-PV, Doffin A-C, Berthet J, et al. IFN-III is selectively produced by cDC1 and predicts good clinical outcome in breast cancer. Science immunology. 2020;5(46):eaav3942.
33. Zhong Y, Zhuang Z, Mo P, Shang Q, Lin M, Gong J, et al. Overexpression of MAL2 correlates with immune infiltration and poor prognosis in breast cancer. Evidence‐Based Complementary and Alternative Medicine. 2021;2021(1):5557873.
34. Liao Y-h, Chen L, Feng B-h, Lv W, Huang X-p, Li H, et al. Revelation of comprehensive cell profiling of primary and metastatic tumour ecosystems in oral squamous cell carcinoma by single-cell transcriptomic analysis. International Journal of Medical Sciences. 2024;21(12):2293.
35. Kumar S, Singh A, Chaudhary A, Singh RK, Shanker A, Kumar V, et al. Neoantigen identification and dendritic cell-based vaccines for lung cancer immunotherapy. Vaccines. 2024;12(5):498.
36. Khalil M. Defining Memory NK Cell Development and Functions Following Cytomegalovirus Infection: The Medical College of Wisconsin; 2024.
37. Huntington ND, Cursons J, Rautela J. The cancer–natural killer cell immunity cycle. Nature Reviews Cancer. 2020;20(8):437-54.
38. Fionda C, Scarno G, Stabile H, Molfetta R, Di Censo C, Gismondi A, et al. NK cells and other cytotoxic innate lymphocytes in colorectal cancer progression and metastasis. International journal of molecular sciences. 2022;23(14):7859.
39. Duault C, Kumar A, Taghi Khani A, Lee SJ, Yang L, Huang M, et al. Activated natural killer cells predict poor clinical prognosis in high-risk B-and T-cell acute lymphoblastic leukemia. Blood, The Journal of the American Society of Hematology. 2021;138(16):1465-80.
40. Cantoni C, Wurzer H, Thomas C, Vitale M. Escape of tumor cells from the NK cell cytotoxic activity. Journal of Leucocyte Biology. 2020;108(4):1339-60.
41. Paul S, Chhatar S, Mishra A, Lal G. Natural killer T cell activation increases iNOS+ CD206-M1 macrophage and controls the growth of solid tumor. Journal for immunotherapy of cancer. 2019;7(1):208.
42. Wu Y, Zheng Y, Jin Z. ANGPTL3 affects the metastatic potential and the susceptibility of ovarian cancer cells to natural killer cell-mediated cytotoxicity. Heliyon. 2023;9(8).
43. Bassani B, Baci D, Gallazzi M, Poggi A, Bruno A, Mortara L. Natural killer cells as key players of tumor progression and angiogenesis: old and novel tools to divert their pro-tumor activities into potent anti-tumor effects. Cancers. 2019;11(4):461.
44. He S, Zheng L, Qi C. Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment and their targeting in cancer therapy. Molecular cancer. 2025;24(1):5.
45. Hofer F, Di Sario G, Musiu C, Sartoris S, De Sanctis F, Ugel S. A complex metabolic network confers immunosuppressive functions to myeloid-derived suppressor cells (MDSCs) within the tumour microenvironment. Cells. 2021;10(10):2700.
46. Vanhaver C, van der Bruggen P, Bruger AM. MDSC in mice and men: mechanisms of immunosuppression in cancer. Journal of clinical medicine. 2021;10(13):2872.
47. Law AM, Valdes-Mora F, Gallego-Ortega D. Myeloid-derived suppressor cells as a therapeutic target for cancer. Cells. 2020;9(3):561.
48. Liu H, Wang Z, Zhou Y, Yang Y. MDSCs in breast cancer: an important enabler of tumor progression and an emerging therapeutic target. Frontiers in Immunology. 2023;14:1199273.
49. Lian H, Zhang J, Hou S, Ma S, Yu J, Zhao W, et al. Immunotherapy of osteosarcoma based on immune microenvironment modulation. Frontiers in Immunology. 2025;15:1498060.
50. Xiong D, Yin Z, Huang M, Wang Y, Hardy M, Kalyanaraman B, et al. Mitochondria‐targeted atovaquone promotes anti‐lung cancer immunity by reshaping tumor microenvironment and enhancing energy metabolism of anti‐tumor immune cells. Cancer Communications. 2023;44(3):448.
51. Ke C-H, Chiu Y-H, Huang K-C, Lin C-S. Exposure of immunogenic tumor antigens in surrendered immunity and the significance of autologous tumor cell-based vaccination in precision medicine. International journal of molecular sciences. 2022;24(1):147.
52. Basu A, Ramamoorthi G, Albert G, Gallen C, Beyer A, Snyder C, et al. Differentiation and regulation of TH cells: a balancing act for cancer immunotherapy. Frontiers in immunology. 2021;12:669474.
53. Teillaud J-L, Houel A, Panouillot M, Riffard C, Dieu-Nosjean M-C. Tertiary lymphoid structures in anticancer immunity. Nature Reviews Cancer. 2024;24(9):629-46.
54. Couturaud B. Impact of TCR-ligand avidity for viral and tumor antigens on human CD8 T cell potency and long-term persistence: Université de Lausanne, Faculté de biologie et médecine; 2019.
55. Oh DY, Fong L. Cytotoxic CD4+ T cells in cancer: Expanding the immune effector toolbox. Immunity. 2021;54(12):2701-11.
56. Zeng S, Hu H, Li Z, Hu Q, Shen R, Li M, et al. Local TSH/TSHR signaling promotes CD8+ T cell exhaustion and immune evasion in colorectal carcinoma. Cancer Communications. 2024;44(11):1287-310.
57. Kuwahara T, Hazama S, Suzuki N, Yoshida S, Tomochika S, Nakagami Y, et al. Intratumoural-infiltrating CD4+ and FOXP3+ T cells as strong positive predictive markers for the prognosis of resectable colorectal cancer. British journal of cancer. 2019;121(8):659-65.
58. Qin M, Jin Y, Pan L-Y. Tertiary lymphoid structure and B-cell-related pathways: A potential target in tumor immunotherapy. Oncology letters. 2021;22(6):836.
59. Chen W, Zhang L, Gao M, Zhang N, Wang R, Liu Y, et al. Role of tertiary lymphoid structures and B cells in clinical immunotherapy of gastric cancer. Frontiers in Immunology. 2025;15:1519034.
60. Shiravand Y, Khodadadi F, Kashani SMA, Hosseini-Fard SR, Hosseini S, Sadeghirad H, et al. Immune checkpoint inhibitors in cancer therapy. Current Oncology. 2022;29(5):3044-60.
61. Tian C, Wang X, Zhang S. CTLA-4 and its inhibitors in esophageal cancer: efficacy of therapy and potential mechanisms of adverse events. American Journal of Cancer Research. 2023;13(7):3140.
62. Borelli B, Antoniotti C, Carullo M, Germani MM, Conca V, Masi G. Immune-checkpoint inhibitors (ICIs) in metastatic colorectal cancer (mCRC) patients beyond microsatellite instability. Cancers. 2022;14(20):4974.
63. Zhang P, Zhang G, Wan X. Challenges and new technologies in adoptive cell therapy. Journal of hematology & oncology. 2023;16(1):97.
64. Strohl WR, Naso M. Bispecific T-cell redirection versus chimeric antigen receptor (CAR)-T cells as approaches to kill cancer cells. Antibodies. 2019;8(3):41.
65. Tojjari A, Hafez AH, Saeed A, Singh M, Saeed A. Exploring glypican-3 as a molecular target in hepatocellular carcinoma: perspectives on diagnosis and precision immunotherapy strategies. Frontiers in Bioscience-Landmark. 2024;29(7):268.
66. Rohaan MW, Borch TH, Van Den Berg JH, Met Ö, Kessels R, Geukes Foppen MH, et al. Tumor-infiltrating lymphocyte therapy or ipilimumab in advanced melanoma. New England Journal of Medicine. 2022;387(23):2113-25.
67. Buongiorno L, Tagliamonte M. Selecting target antigens for cancer vaccine development. Vaccines. 2020;8(4):615.
68. Cao F, Xu Y, Guan Y, Zhang K, Qiu H, Xu Z, et al. Enhancing the potency of 5T4 mRNA vaccine by CD70 mRNA-LNPs through ADCC and T cell boosting in prostate cancer therapy. Journal of Nanobiotechnology. 2025;23(1):523.
69. Huang X, Zhang G, Tang T-Y, Gao X, Liang T-B. Personalized pancreatic cancer therapy: from the perspective of mRNA vaccine. Military Medical Research. 2022;9(1):53.
70. Sutherland SI, Ju X, Horvath L, Clark GJ. Moving on from sipuleucel-T: new dendritic cell vaccine strategies for prostate cancer. Frontiers in immunology. 2021;12:641307.
71. Zhang F, Huang D, Zhao L, Li T, Zhang S, Zhang G, et al. Efficacy and safety of PD-1/PD-L1 inhibitors plus nab-paclitaxel for patients with non-small cell lung cancer who have progressed after platinum-based chemotherapy. Therapeutic advances in medical oncology. 2020;12:1758835920936882.
72. Zhang H, Huang J, Xu H, Yin N, Zhou L, Xue J, et al. Neoadjuvant immunotherapy for DNA mismatch repair proficient/microsatellite stable non-metastatic rectal cancer: a systematic review and meta-analysis. Frontiers in Immunology. 2025;16:1523455.
73. Peng M, Xiao D, Bu Y, Long J, Yang X, Lv S, et al. Novel combination therapies for the treatment of bladder cancer. Frontiers in Oncology. 2021;10:539527.
74. Zhang B, Tao B, Li Y, Yi C, Lin Z, Ma Y, et al. Dual immune checkpoint inhibitors or combined with anti-VEGF agents in advanced, unresectable hepatocellular carcinoma. European Journal of Internal Medicine. 2023;111:37-46.
75. García-Sancha N, Corchado-Cobos R, Bellido-Hernández L, Román-Curto C, Cardeñoso-Álvarez E, Pérez-Losada J, et al. Overcoming resistance to immunotherapy in advanced cutaneous squamous cell carcinoma. Cancers. 2021;13(20):5134.
76. Jackson C, Cherry C, Bom S, Dykema AG, Thompson E, Zheng M, et al. Distinct myeloid derived suppressor cell populations promote tumor aggression in glioblastoma. bioRxiv. 2023:2023.03. 26.534192.
77. Elhanani O, Ben-Uri R, Keren L. Spatial profiling technologies illuminate the tumor microenvironment. Cancer cell. 2023;41(3):404-20.
78. Ibekwe P-MR, Akintayo EA, Okuku CN, Muhammed I, Jeje FM, Oseghale O, et al. Decoding tumor heterogeneity through multi omics: Insights into cancer evolution, microenvironment and therapy resistance. Journal of Cancer and Tumor International. 2025;15(3):91-112.
