Cancer Cell-Intrinsic Programs That Shape Tumor Immune Ecosystems

Lijian Wang; Yutong Guo; Lingchuan Ma; Kai Miao

doi:10.66505/cbtt.v1i2.33

Authors

Lijian Wang
Yutong Guo
Lingchuan Ma
Kai Miao https://orcid.org/0000-0003-4832-3354

DOI:

https://doi.org/10.66505/cbtt.v1i2.33

Keywords:

tumor microenvironment, oncogenic signaling, metabolic reprogramming, epigenetic regulation, immune evasion, cancer immunotherapy, tumor immunology

Abstract

The tumor immune microenvironment (TIME) is a highly dynamic ecosystem that critically influences tumor progression, metastatic dissemination, and therapeutic responsiveness. Classical models of tumor biology have long been framed by the “seed and soil” paradigm, in which malignant cells represent passive “seeds” growing within a permissive or restrictive microenvironmental “soil.” However, accumulating evidence indicates that this framework is incomplete. Tumor cells are not merely shaped by their environment but actively orchestrate the immune landscape through intrinsic molecular programs. In this review, we synthesize emerging evidence supporting a revised paradigm in which cancer cell-intrinsic drivers, including oncogenic signaling pathways, metabolic reprogramming, and epigenetic alterations, act as central regulators of the TIME. These intrinsic programs enable malignant cells to rewire immune surveillance by suppressing cytotoxic lymphocyte function, promoting the recruitment and polarization of immunosuppressive myeloid populations, and establishing metabolic and structural barriers that limit effective antitumor immunity. Recent technological advances, particularly single-cell transcriptomics, spatially resolved profiling, and multi-omic approaches, have provided unprecedented insight into how these tumor-cell programs reshape immune architecture across spatial niches within tumors. We discuss how these mechanisms collectively generate immunosuppressive microenvironments that underlie resistance to immune checkpoint blockade and other immunotherapies. Finally, we highlight emerging therapeutic strategies aimed at targeting cancer cell-intrinsic drivers to reprogram the TIME, emphasizing the potential of rational combination approaches that simultaneously modulate tumor signaling, metabolism, and immune activation. Understanding cancer cells as active architects of their immune ecosystem provides a conceptual framework for the next generation of precision immunotherapies.

References

1. Zhan H, Wang H, Pan B, Lu J, Xiao K, Lai J, et al. Reprogramming the tumor microenvironment with c-MYC-based gene circuit platform to enhance specific cancer immunotherapy. Nat Commun. 2025;16(1):7983. doi:10.1038/s41467-025-63377-3

2. Li Y, Casey SC, Felsher DW. Inactivation of MYC reverses tumorigenesis. J Intern Med. 2014;276(1):52-60. doi:10.1111/joim.12237

3. Casey SC, Tong L, Li Y, Do R, Walz S, Fitzgerald KN, et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science. 2016;352(6282):227-231. doi:10.1126/science.aac9935

4. Kim EY, Kim A, Kim SK, Chang YS. MYC expression correlates with PD-L1 expression in non-small cell lung cancer. Lung Cancer. 2017;110:63-67. doi:10.1016/j.lungcan.2017.06.006

5. Wu SY, Xiao Y, Wei JL, Xu XE, Jin X, Hu X, et al. MYC suppresses STING-dependent innate immunity by transcriptionally upregulating DNMT1 in triple-negative breast cancer. J Immunother Cancer. 2021;9(7):e002528. doi:10.1136/jitc-2021-002528

6. Jiang K, Zhang Q, Fan Y, Li J, Zhang J, Wang W, et al. MYC inhibition reprograms tumor immune microenvironment by recruiting T lymphocytes and activating the CD40/CD40L system in osteosarcoma. Cell Death Discov. 2022;8(1):117. doi:10.1038/s41420-022-00923-8

7. De Sanctis F, Adamo A, Canè S, Ugel S. Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy. Semin Immunopathol. 2023;45(2):163-186. doi:10.1007/s00281-022-00965-1

8. Tannenbaum CS, Rayman PA, Pavicic PG, Kim JS, Wei W, Polefko A, et al. Mediators of inflammation-driven expansion, trafficking, and function of tumor-infiltrating MDSCs. Cancer Immunol Res. 2019;7(10):1687-1699. doi:10.1158/2326-6066.cir-18-0578

9. Hu H, Yang M, Huang B, Ding J, Zhu Y, Xu X, et al. Tumor cells promote immunosuppression in ovarian cancer via a positive feedback loop with MDSCs through the SAA1-IL-1β axis. J Exp Clin Cancer Res. 2025;44(1):277. doi:10.1186/s13046-025-03536-y

10. Silva-Romeiro S, Flores-Campos RDC, Sánchez-León ML, Sánchez-Margalet V, De la Cruz-Merino L. Emerging role of MDSCs as novel biomarkers and therapeutic targets for cancer immunotherapy. Immunotargets Ther. 2025;14:1267-1291. doi:10.2147/itt.S485642

11. Caetano MS, Zhang H, Cumpian AM, Gong L, Unver N, Ostrin EJ, et al. IL6 blockade reprograms the lung tumor microenvironment to limit the development and progression of K-ras-mutant lung cancer. Cancer Res. 2016;76(11):3189-3199. doi:10.1158/0008-5472.can-15-2840

12. Weber R, Riester Z, Hüser L, Sticht C, Siebenmorgen A, Groth C, et al. IL-6 regulates CCR5 expression and immunosuppressive capacity of MDSC in murine melanoma. J Immunother Cancer. 2020;8(2):e000949. doi:10.1136/jitc-2020-000949

13. Yenyuwadee S, Aliazis K, Wang Q, Christofides A, Shah R, Patsoukis N, et al. Immune cellular components and signaling pathways in the tumor microenvironment. Semin Cancer Biol. 2022;86(Pt2):187-201. doi:10.1016/j.semcancer.2022.08.004

14. Nguyen HT, Kan EL, Humayun M, Gurvich N, Offeddu GS, Wan Z, et al. Patient-specific vascularized tumor model: blocking monocyte recruitment with multispecific antibodies targeting CCR2 and CSF-1R. Biomaterials. 2025;312:122731. doi:10.1016/j.biomaterials.2024.122731

15. Zhou Y, Zeng J, Tu Y, Li L, Du S, Zhu L, et al. CSF1/CSF1R-mediated crosstalk between choroidal vascular endothelial cells and macrophages promotes choroidal neovascularization. Invest Ophthalmol Vis Sci. 2021;62(3):37. doi:10.1167/iovs.62.3.37

16. Nirala BK, Patel TD, Kurenbekova L, Shuck R, Dasgupta A, Rainusso N, et al. MYC regulates CSF1 expression via microRNA 17/20a to modulate tumor-associated macrophages in osteosarcoma. JCI Insight. 2023;8(13):e164947. doi:10.1172/jci.insight.164947

17. Dang T, You Y, Wei L, Li Q, Sun H, Sun M, et al. ICAT drives lactylation of tumor-associated macrophages via the c-Myc-ENO1 axis to promote cervical cancer progression. Free Radic Biol Med. 2025;241:316-329. doi:10.1016/j.freeradbiomed.2025.09.031

18. Colombo M, Garavelli S, Mazzola M, Platonova N, Giannandrea D, Colella R, et al. Multiple myeloma exploits Jagged1 and Jagged2 to promote intrinsic and bone marrow-dependent drug resistance. Haematologica. 2020;105(7):1925-1936. doi:10.3324/haematol.2019.221077

19. Xia Y, Huang C, Zhong M, Zhong H, Ruan R, Xiong J, et al. Targeting HGF/c-MET signaling to regulate the tumor microenvironment: implications for counteracting tumor immune evasion. Cell Commun Signal. 2025;23(1):46. doi:10.1186/s12964-025-02033-1

20. Simanshu DK, Nissley DV, McCormick F. RAS proteins and their regulators in human disease. Cell. 2017;170(1):17-33. doi:10.1016/j.cell.2017.06.009

21. Prior IA, Hood FE, Hartley JL. The frequency of Ras mutations in cancer. Cancer Res. 2020;80(14):2969-2974. doi:10.1158/0008-5472.can-19-3682

22. Bos JL. RAS oncogenes in human cancer: a review. Cancer Res. 1989;49(17):4682-4689. PMID: 2547513.

23. Downward J. RAS signalling pathways in cancer therapy. Nat Rev Cancer. 2003;3(1):11-22. doi:10.1038/nrc969

24. Sparmann A, Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell. 2004;6(5):447-458. doi:10.1016/j.ccr.2004.09.028

25. Ancrile B, Lim KH, Counter CM. Oncogenic Ras-induced secretion of IL6 is required for tumorigenesis. Genes Dev. 2007;21(14):1714-1719. doi:10.1101/gad.1549407

26. Leslie K, Gao SP, Berishaj M, Podsypanina K, Ho H, Ivashkiv L, et al. Differential interleukin-6/Stat3 signaling as a function of cellular context mediates Ras-induced transformation. Breast Cancer Res. 2010;12(5):R80. doi:10.1186/bcr2725

27. Pylayeva-Gupta Y, Lee KE, Hajdu CH, Miller G, Bar-Sagi D. Oncogenic Kras-induced GM-CSF production promotes the development of pancreatic neoplasia. Cancer Cell. 2012;21(6):836-847. doi:10.1016/j.ccr.2012.04.024

28. Cox AD, Olive KP. Silencing the killers: paracrine immune suppression in pancreatic cancer. Cancer Cell. 2012;21(6):715-716. doi:10.1016/j.ccr.2012.05.029

29. Ramirez CFA, Taranto D, Ando-Kuri M, de Groot MHP, Tsouri E, Huang Z, et al. Cancer cell genetics shaping of the tumor microenvironment reveals myeloid cell-centric exploitable vulnerabilities in hepatocellular carcinoma. Nat Commun. 2024;15(1):2581. doi:10.1038/s41467-024-46835-2

30. Elliot AM, Ribeiro Bravo I, Zhao Y, Wang Z, Astorga Johansson J, Hutton E, et al. Oncogenic Ras activation in permissive somatic cells triggers rapid-onset phenotypic plasticity and elicits a tumor-promoting neutrophil response. Cell Rep. 2025;44(11):116478. doi:10.1016/j.celrep.2025.116478

31. Lahusen A, Minhöfer N, Lohse KA, Blechner C, Lindenmayer J, Eiseler T, et al. Pancreatic cancer cell-intrinsic transglutaminase-2 promotes T cell suppression through microtubule-dependent secretion of immunosuppressive cytokines. J Immunother Cancer. 2025;13(5):e010579. doi:10.1136/jitc-2024-010579

32. Kim BS, Clinton J, Wang Q, Chang SH. Targeting ST2 expressing activated regulatory T cells in Kras-mutant lung cancer. Oncoimmunology. 2020;9(1):1682380. doi:10.1080/2162402x.2019.1682380

33. Hua H, He W, Chen N, He Y, Wu G, Ye F, et al. Genomic and transcriptomic analysis of MSI-H colorectal cancer patients with targetable alterations identifies clinical implications for immunotherapy. Front Immunol. 2023;13:974793. doi:10.3389/fimmu.2022.974793

34. Huang K, Han Y, Chen Y, Shen H, Zeng S, Cai C. Tumor metabolic regulators: key drivers of metabolic reprogramming and the promising targets in cancer therapy. Mol Cancer. 2025;24(1):7. doi:10.1186/s12943-024-02205-6

35. Xie Z, Zhou Z, Yang S, Zhang S, Shao B. Epigenetic regulation and therapeutic targets in the tumor microenvironment. Mol Biomed. 2023;4(1):17. doi:10.1186/s43556-023-00126-2

36. Sivakumar S, Jainarayanan A, Arbe-Barnes E, Sharma PK, Leathlobhair MN, Amin S, et al. Distinct immune cell infiltration patterns in pancreatic ductal adenocarcinoma (PDAC) exhibit divergent immune cell selection and immunosuppressive mechanisms. Nat Commun. 2025;16(1):1397. doi:10.1038/s41467-024-55424-2

37. Mantovani F, Collavin L, Del Sal G. Mutant p53 as a guardian of the cancer cell. Cell Death Differ. 2019;26(2):199-212. doi:10.1038/s41418-018-0246-9

38. Chen X, Zhang T, Su W, Dou Z, Zhao D, Jin X, et al. Mutant p53 in cancer: from molecular mechanism to therapeutic modulation. Cell Death Dis. 2022;13(11):974. doi:10.1038/s41419-022-05408-1

39. Liu S, Liu T, Jiang J, Guo H, Yang R. p53 mutation and deletion contribute to tumor immune evasion. Front Genet. 2023;14:1088455. doi:10.3389/fgene.2023.1088455

40. Zhao W, Nguyen TT, Bhagwat A, Kumar A, Giotti B, Kepecs B, et al. A cellular and spatial atlas of TP53-associated tissue remodeling defines a multicellular tumor ecosystem in lung adenocarcinoma. Nat Cancer. 2025;6(11):1857-1879. doi:10.1038/s43018-025-01053-7

41. Bernatowicz K, Amat R, Prior O, Frigola J, Ligero M, Grussu F, et al. Radiomics signature for dynamic monitoring of tumor inflamed microenvironment and immunotherapy response prediction. J Immunother Cancer. 2025;13(1):e009140. doi:10.1136/jitc-2024-009140

42. Wang C, Tan JYM, Chitkara N, Bhatt S. TP53 mutation-mediated immune evasion in cancer: mechanisms and therapeutic implications. Cancers (Basel). 2024;16(17):3069. doi:10.3390/cancers16173069

43. Kim H, Shim BY, Lee SJ, Lee JY, Lee HJ, Kim IH. Loss of Von Hippel-Lindau (VHL) tumor suppressor gene function: VHL-HIF pathway and advances in treatments for metastatic renal cell carcinoma. Int J Mol Sci. 2021;22(18):9795. doi:10.3390/ijms22189795

44. Shen J, Ju Z, Zhao W. ARID1A deficiency promotes mutability and potentiates therapeutic antitumor immunity unleashed by immune checkpoint blockade. Nat Med. 2018;24(5):556-562. doi:10.1038/s41591-018-0012-z

45. Kessler J, Hohmann T, Güttler A, Petrenko M, Ostheimer C, Hohmann U, et al. Radiosensitization and a less aggressive phenotype of human malignant glioma cells expressing isocitrate dehydrogenase 1 (IDH1) mutant protein: dissecting the mechanisms. Cancers (Basel). 2019;11(6):889. doi:10.3390/cancers11060889

46. Kadiyala P, Carney SV, Gauss JC, Garcia-Fabiani MB, Haase S, Alghamri MS, et al. Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice. J Clin Invest. 2021;131(4):e139542. doi:10.1172/jci139542

47. Kraya AA, Maxwell KN, Wubbenhorst B, Wenz BM, Pluta J, Rech AJ, et al. Genomic signatures predict the immunogenicity of BRCA-deficient breast cancer. Clin Cancer Res. 2019;25(14):4363-4374. doi:10.1158/1078-0432.ccr-18-0468

48. Shi C, Qin K, Lin A, Jiang A, Cheng Q, Liu Z, et al. The role of DNA damage repair (DDR) system in response to immune checkpoint inhibitor (ICI) therapy. J Exp Clin Cancer Res. 2022;41(1):268. doi:10.1186/s13046-022-02469-0

49. Sircar A, Singh S, Xu-Monette ZY, Coyle KM, Hilton LK, Chavdoula E, et al. Exploiting the fibroblast growth factor receptor-1 vulnerability to therapeutically restrict the MYC-EZH2-CDKN1C axis-driven proliferation in mantle cell lymphoma. Leukemia. 2023;37(10):2094-2106. doi:10.1038/s41375-023-02006-8

50. Lin HH, Chang CW, Liao YT, Yeh SD, Lin HP, Ho HM, et al. DUSP22 inhibits lung tumorigenesis by suppression of EGFR/c-Met signaling. Cell Death Discov. 2024;10(1):285. doi:10.1038/s41420-024-02038-8

51. Luchtel RA, Dasari S, Oishi N, Pedersen MB, Hu G, Rech KL, et al. Molecular profiling reveals immunogenic cues in anaplastic large cell lymphomas with DUSP22 rearrangements. Blood. 2018;132(13):1386-1398. doi:10.1182/blood-2018-03-838524

52. Wang L, Guo Y, Dai Y, Sun W, Huang X, Lei H, et al. DUSP22 dephosphorylates LGALS1 to enhance T cell-driven antitumor immunity. J Immunother Cancer. 2026;14(1):e013142. doi:10.1136/jitc-2025-013142

53. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. doi:10.1016/j.cell.2011.02.013

54. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324(5930):1029-1033. doi:10.1126/science.1160809

55. Chen J, Huang Z, Chen Y, Tian H, Chai P, Shen Y, et al. Lactate and lactylation in cancer. Signal Transduct Target Ther. 2025;10(1):38. doi:10.1038/s41392-024-02082-x

56. Feng Q, Bennett Z, Grichuk A, Pantoja R, Huang T, Faubert B, et al. Severely polarized extracellular acidity around tumour cells. Nat Biomed Eng. 2024;8(7):787-799. doi:10.1038/s41551-024-01178-7

57. Liu PS, Wang H, Li X, Chao T, Teav T, Christen S, et al. α-ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat Immunol. 2017;18(9):985-994. doi:10.1038/ni.3796

58. De Martino M, Rathmell JC, Galluzzi L, Vanpouille-Box C. Cancer cell metabolism and antitumour immunity. Nat Rev Immunol. 2024;24(10):654-669. doi:10.1038/s41577-024-01026-4

59. Guo C, You Z, Shi H, Sun Y, Du X, Palacios G, et al. SLC38A2 and glutamine signalling in cDC1s dictate anti-tumour immunity. Nature. 2023;620(7972):200-208. doi:10.1038/s41586-023-06299-8

60. Lin Z, Chang C, Zhao S, Fang L, Wang P. Amino acids shape the metabolic and immunologic landscape in the tumor immune microenvironment: from molecular mechanisms to therapeutic strategies. Cancer Biol Med. 2025;22(4):726-746. doi:10.20892/j.issn.2095-3941.2025.0115

61. Lv Y, Li Z, Liu S, Zhou Z, Song J, Ba Y, et al. Metabolic checkpoints in immune cell reprogramming: rewiring immunometabolism for cancer therapy. Mol Cancer. 2025;24(1):210. doi:10.1186/s12943-025-02407-6

62. Menjivar RE, Nwosu ZC, Du W, Donahue KL, Hong HS, Espinoza C, et al. Arginase 1 is a key driver of immune suppression in pancreatic cancer. eLife. 2023;12:e80721. doi:10.7554/elife.80721

63. Zhu Y, Zhou Z, Du X, Lin X, Liang ZM, Chen S, et al. Cancer cell-derived arginine fuels polyamine biosynthesis in tumor-associated macrophages to promote immune evasion. Cancer Cell. 2025;43(6):1045-1060.e7. doi:10.1016/j.ccell.2025.03.015

64. Srivastava S, Anbiaee R, Houshyari M, Laxmi, Sridhar SB, Ashique S, et al. Amino acid metabolism in glioblastoma pathogenesis, immune evasion, and treatment resistance. Cancer Cell Int. 2025;25(1):89. doi:10.1186/s12935-025-03721-1

65. Fallarino F, Grohmann U, Vacca C, Bianchi R, Orabona C, Spreca A, et al. T cell apoptosis by tryptophan catabolism. Cell Death Differ. 2002;9(10):1069-1077. doi:10.1038/sj.cdd.4401073

66. Chen W, Liang X, Peterson AJ, Munn DH, Blazar BR. The indoleamine 2,3-dioxygenase pathway is essential for human plasmacytoid dendritic cell-induced adaptive T regulatory cell generation. J Immunol. 2008;181(8):5396-5404. doi:10.4049/jimmunol.181.8.5396

67. Bian Y, Li W, Kremer DM, Sajjakulnukit P, Li S, Crespo J, et al. Cancer SLC43A2 alters T cell methionine metabolism and histone methylation. Nature. 2020;585(7824):277-282. doi:10.1038/s41586-020-2682-1

68. Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351(6268):43-48. doi:10.1126/science.aab2674

69. Chantranupong L, Scaria SM, Saxton RA, Gygi MP, Shen K, Wyant GA, et al. The CASTOR proteins are arginine sensors for the mTORC1 pathway. Cell. 2016;165(1):153-164. doi:10.1016/j.cell.2016.02.035

70. Zhang Y, Hu H, Liu W, Yan SM, Li Y, Tan L, et al. Amino acids and RagD potentiate mTORC1 activation in CD8+ T cells to confer antitumor immunity. J Immunother Cancer. 2021;9(4):e002137. doi:10.1136/jitc-2020-002137

71. Dai X, Yan P, Wei W. Amino acid availability governs mTOR ubiquitination. Cell Res. 2024;34(4):335-336. doi:10.1038/s41422-023-00910-3

72. Ge MK, Zhang C, Zhang N, He P, Cai HY, Li S, et al. The tRNA-GCN2-FBXO22 axis-mediated mTOR ubiquitination senses amino acid insufficiency. Cell Metab. 2023;35(12):2216-2230.e8. doi:10.1016/j.cmet.2023.10.016

73. Solvay M, Holfelder P, Klaessens S, Pilotte L, Stroobant V, Lamy J, et al. Tryptophan depletion sensitizes the AHR pathway by increasing AHR expression and GCN2/LAT1-mediated kynurenine uptake, and potentiates induction of regulatory T lymphocytes. J Immunother Cancer. 2023;11(6):e006728. doi:10.1136/jitc-2023-006728

74. Mezrich JD, Fechner JH, Zhang X, Johnson BP, Burlingham WJ, Bradfield CA. An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells. J Immunol. 2010;185(6):3190-3198. doi:10.4049/jimmunol.0903670

75. Opitz CA, Litzenburger UM, Sahm F, Ott M, Tritschler I, Trump S, et al. An endogenous tumour-promoting ligand of the human aryl hydrocarbon receptor. Nature. 2011;478(7368):197-203. doi:10.1038/nature10491

76. Quintana FJ, Basso AS, Iglesias AH, Korn T, Farez MF, Bettelli E, et al. Control of Treg and TH17 cell differentiation by the aryl hydrocarbon receptor. Nature. 2008;453(7191):65-71. doi:10.1038/nature06880

77. Jin J, Meng T, Yu Y, Wu S, Jiao CC, Song S, et al. Human HDAC6 senses valine abundancy to regulate DNA damage. Nature. 2025;637(8046):215-223. doi:10.1038/s41586-024-08248-5

78. Kim SH, Choi JH, Wang P, Go CD, Hesketh GG, Gingras AC, et al. Mitochondrial threonyl-tRNA synthetase TARS2 is required for threonine-sensitive mTORC1 activation. Mol Cell. 2021;81(2):398-407.e4. doi:10.1016/j.molcel.2020.11.036

79. Sung Y, Yu YC, Han JM. Nutrient sensors and their crosstalk. Exp Mol Med. 2023;55(6):1076-1089. doi:10.1038/s12276-023-01006-z

80. Yang K, Wang X, Song C, He Z, Wang R, Xu Y, et al. The role of lipid metabolic reprogramming in tumor microenvironment. Theranostics. 2023;13(5):1774-1808. doi:10.7150/thno.82920

81. Frauwirth KA, Riley JL, Harris MH, Parry RV, Rathmell JC, Plas DR, et al. The CD28 signaling pathway regulates glucose metabolism. Immunity. 2002;16(6):769-777. doi:10.1016/S1074-7613(02)00323-0

82. Chamoto K, Chowdhury PS, Kumar A, Sonomura K, Matsuda F, Fagarasan S, et al. Mitochondrial activation chemicals synergize with surface receptor PD-1 blockade for T cell-dependent antitumor activity. Proc Natl Acad Sci U S A. 2017;114(5):E761-E770. doi:10.1073/pnas.1620433114

83. Hunt EG, Hurst KE, Riesenberg BP, Kennedy AS, Gandy EJ, Andrews AM, et al. Acetyl-CoA carboxylase obstructs CD8+ T cell lipid utilization in the tumor microenvironment. Cell Metab. 2024;36(5):969-983.e10. doi:10.1016/j.cmet.2024.02.009

84. Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity. 2016;45(2):701-713. doi:10.1016/j.immuni.2016.08.009

85. Siska PJ, van der Windt GJW, Kishton RJ, Cohen S, Eisner W, MacIver NJ, et al. Suppression of glut1 and glucose metabolism by decreased Akt/mTORC1 signaling drives T cell impairment in the tumor microenvironment. J Immunol. 2016 Sep 15;197(6):2532-40. doi:10.4049/jimmunol.1502464

86. Kedia-Mehta N, Finlay DK. Competition for nutrients and its role in controlling immune responses. Nat Commun. 2019;10(1):2123. doi:10.1038/s41467-019-10015-4

87. Wang Y, Liu M, Zhang L, Liu X, Ji H, Wang Y, et al. Cancer CD39 drives metabolic adaption and mal-differentiation of CD4+ T cells in patients with non-small-cell lung cancer. Cell Death Dis. 2023;14(12):804. doi:10.1038/s41419-023-06336-4

88. Wang H, Zhou F, Qin W, Yang Y, Li X, Liu R. Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies. Theranostics. 2025;15(5):2159-2184. doi:10.7150/thno.105276

89. Corn KC, Windham MA, Rafat M. Lipids in the tumor microenvironment: from cancer progression to treatment. Prog Lipid Res. 2020;80:101055. doi:10.1016/j.plipres.2020.101055

90. Li Y, You J, Zou Z, Sun G, Shi Y, Sun Y, et al. Decoding the tumor microenvironment: exosome-mediated macrophage polarization and therapeutic frontiers. Int J Biol Sci. 2025;21(11):4187-4214. doi:10.7150/ijbs.114222

91. 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. Biomark Res. 2024;12(1):1. doi:10.1186/s40364-023-00549-7

92. Xu B, Liu Y, Li N, Geng Q. Lactate and lactylation in macrophage metabolic reprogramming: current progress and outstanding issues. Front Immunol. 2024;15:1395786. doi:10.3389/fimmu.2024.1395786

93. 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. Int J Biol Sci. 2023;19(15):4915-4930. doi:10.7150/ijbs.86039

94. Zhang X, Ye X, Jin H. Oxidized low-density lipoprotein as a potential target for enhancing immune checkpoint inhibitor therapy in microsatellite-stable colorectal cancer. Antioxidants (Basel). 2025;14(6):726. doi:10.3390/antiox14060726

95. Wellen KE, Thompson CB. Cellular metabolic stress: considering how cells respond to nutrient excess. Mol Cell. 2010;40(2):323-332. doi:10.1016/j.molcel.2010.10.004

96. Bensaad K, Favaro E, Lewis CA, Peck B, Lord S, Collins JM, et al. Fatty acid uptake and lipid storage induced by HIF-1α contribute to cell growth and survival after hypoxia-reoxygenation. Cell Rep. 2014;9(1):349-365. doi:10.1016/j.celrep.2014.08.056

97. Ye L, Wen X, Qin J, Zhang X, Wang Y, Wang Z, et al. Metabolism-regulated ferroptosis in cancer progression and therapy. Cell Death Dis. 2024;15(3):196. doi:10.1038/s41419-024-06584-y

98. Lancaster GI, Murphy AJ. Do physiological changes in fatty acid composition alter cellular ferroptosis susceptibility and influence cell function? J Lipid Res. 2025;66(4):100765. doi:10.1016/j.jlr.2025.100765

99. Wang P, Zhang S, Chen X, Yang XD, Huang S, Yin H, et al. Tumor cell-specific loss of GPX4 reprograms triacylglycerol metabolism to escape ferroptosis and impair antitumor immunity in non-small cell lung cancer. Protein Cell. 2025;pwaf101. doi:10.1093/procel/pwaf101

100. Li W, Li F, Zhang X, Lin HK, Xu C. Insights into the post-translational modification and its emerging role in shaping the tumor microenvironment. Signal Transduct Target Ther. 2021;6(1):422. doi:10.1038/s41392-021-00825-8

101. Yao H, Lan J, Li C, Shi H, Brosseau JP, Wang H, et al. Inhibiting PD-L1 palmitoylation enhances T-cell immune responses against tumours. Nat Biomed Eng. 2019;3(4):306-317. doi:10.1038/s41551-019-0375-6

102. Fang Y, Li X. Protein lysine four-carbon acylations in health and disease. J Cell Physiol. 2024;239(3):e30981. doi:10.1002/jcp.30981

103. Ren X, Wang X, Zheng G, Wang S, Wang Q, Yuan M, et al. Targeting one-carbon metabolism for cancer immunotherapy. Clin Transl Med. 2024;14(1):e1521. doi:10.1002/ctm2.1521

104. Sainero-Alcolado L, Liaño-Pons J, Ruiz-Pérez MV, Arsenian-Henriksson M. Targeting mitochondrial metabolism for precision medicine in cancer. Cell Death Differ. 2022;29(7):1304-1317. doi:10.1038/s41418-022-01022-y

105. Luo L, Zheng Y, Lin Z, Li X, Li X, Li M, et al. Identification of SHMT2 as a potential prognostic biomarker and correlating with immune infiltrates in lung adenocarcinoma. J Immunol Res. 2021;2021:6647122. doi:10.1155/2021/6647122

106. Cui L, Chen H, Zhao X. The prognostic significance of immune-related metabolic enzyme MTHFD2 in head and neck squamous cell carcinoma. Diagnostics (Basel). 2020;10(9):689. doi:10.3390/diagnostics10090689

107. Shang M, Yang H, Yang R, Chen T, Fu Y, Li Y, et al. The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation. Nat Commun. 2021;12(1):1940. doi:10.1038/s41467-021-22173-5

108. Hote PT, Sahoo R, Jani TS, Ghare SS, Chen T, Joshi-Barve S, et al. Ethanol inhibits methionine adenosyltransferase II activity and S-adenosylmethionine biosynthesis and enhances caspase-3-dependent cell death in T lymphocytes: relevance to alcohol-induced immunosuppression. J Nutr Biochem. 2008;19(6):384-391. doi:10.1016/j.jnutbio.2007.05.010

109. Si W, Cheng S, He H, Zhang Y, Miao Y, Yi D, et al. SARDH in the 1-C metabolism sculpts the T-cell fate and serves as a potential cancer therapeutic target. Cell Mol Immunol. 2025;22(7):1363-1378. doi:10.1038/s41423-025-01331-5

110. Miret JJ, Kirschmeier P, Koyama S, Zhu M, Li YY, Naito Y, et al. Suppression of myeloid cell arginase activity leads to therapeutic response in a NSCLC mouse model by activating anti-tumor immunity. J Immunother Cancer. 2019;7(1):32. doi:10.1186/s40425-019-0504-5

111. Cai Z, Li W, Hager S, Wilson JL, Afjehi-Sadat L, Heiss EH, et al. Targeting PHGDH reverses the immunosuppressive phenotype of tumor-associated macrophages through α-ketoglutarate and mTORC1 signaling. Cell Mol Immunol. 2024;21(3):448-465. doi:10.1038/s41423-024-01134-0

112. Zhu D, Zeng S, Su C, Li J, Xuan Y, Lin Y, et al. The interaction between DNA methylation and tumor immune microenvironment: from the laboratory to clinical applications. Clin Epigenetics. 2024;16(1):24. doi:10.1186/s13148-024-01633-x

113. Huang Z, Xu J, Wang Y, Fu Z, Zhang Y, Zhao Q, et al. The role of MHC molecules in cancer immunotherapy: insights into tumor immune evasion and therapeutic strategies. Crit Rev Oncol Hematol. 2025;218:105057. doi:10.1016/j.critrevonc.2025.105057

114. Ennishi D, Takata K, Béguelin W, Duns G, Mottok A, Farinha P, et al. Molecular and genetic characterization of MHC deficiency identifies EZH2 as therapeutic target for enhancing immune recognition. Cancer Discov. 2019;9(4):546-563. doi:10.1158/2159-8290.cd-18-1090

115. Burr ML, Sparbier CE, Chan KL, Chan YC, Kersbergen A, Lam EYN, et al. An evolutionarily conserved function of Polycomb silences the MHC class I antigen presentation pathway and enables immune evasion in cancer. Cancer Cell. 2019;36(4):385-401.e8. doi:10.1016/j.ccell.2019.08.008

116. Griffin GK, Wu J, Iracheta-Vellve A, Patti JC, Hsu J, Davis T, et al. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity. Nature. 2021;595(7866):309-314. doi:10.1038/s41586-021-03520-4

117. Kato S, Weng QY, Insco ML, Chen KY, Muralidhar S, Pozniak J, et al. Gain-of-function genetic alterations of G9a drive oncogenesis. Cancer Discov. 2020;10(7):980-997. doi:10.1158/2159-8290.cd-19-0532

118. Seier JA, Reinhardt J, Saraf K, Ng SS, Layer JP, Corvino D, et al. Druggable epigenetic suppression of interferon-induced chemokine expression linked to MYCN amplification in neuroblastoma. J Immunother Cancer. 2021;9(5):e001335. doi:10.1136/jitc-2020-001335

119. Spiliopoulou P, Spear S, Mirza H, Garner I, McGarry L, Grundland-Freile F, et al. Dual G9A/EZH2 inhibition stimulates antitumor immune response in ovarian high-grade serous carcinoma. Mol Cancer Ther. 2022;21(3):522-534. doi:10.1158/1535-7163.mct-21-0743

120. Kelly GM, Al-Ejeh F, McCuaig R, Casciello F, Ahmad Kamal N, Ferguson B, et al. G9a inhibition enhances checkpoint inhibitor blockade response in melanoma. Clin Cancer Res. 2021;27(9):2624-2635. doi:10.1158/1078-0432.ccr-20-3463

121. Xia S, Wu J, Zhou W, Zhang M, Zhao K, Liu J, et al. SLC7A2 deficiency promotes hepatocellular carcinoma progression by enhancing recruitment of myeloid-derived suppressor cells. Cell Death Dis. 2021;12(6):570. doi:10.1038/s41419-021-03853-y

122. Morel KL, Sheahan AV, Burkhart DL, Baca SC, Boufaied N, Liu Y, et al. EZH2 inhibition activates a dsRNA-STING-interferon stress axis that potentiates response to PD-1 checkpoint blockade in prostate cancer. Nat Cancer. 2021;2(4):444-456. doi:10.1038/s43018-021-00185-w

123. Lu M, Zhao B, Liu M, Wu L, Li Y, Zhai Y, et al. Pan-cancer analysis of SETD2 mutation and its association with the efficacy of immunotherapy. NPJ Precis Oncol. 2021;5(1):51. doi:10.1038/s41698-021-00193-0

124. Paschall AV, Yang D, Lu C, Choi JH, Li X, Liu F, et al. H3K9 trimethylation silences Fas expression to confer colon carcinoma immune escape and 5-fluorouracil chemoresistance. J Immunol. 2015;195(4):1868-1882. doi:10.4049/jimmunol.1402243

125. Nguyen EM, Taniguchi H, Chan JM, Zhan YA, Chen X, Qiu J, et al. Targeting lysine-specific demethylase 1 rescues major histocompatibility complex class I antigen presentation and overcomes programmed death-ligand 1 blockade resistance in SCLC. J Thorac Oncol. 2022;17(8):1014-1031. doi:10.1016/j.jtho.2022.05.014

126. Zhou Z, Van der Jeught K, Fang Y, Yu T, Li Y, Ao Z, et al. An organoid-based screen for epigenetic inhibitors that stimulate antigen presentation and potentiate T-cell-mediated cytotoxicity. Nat Biomed Eng. 2021;5(11):1320-1335. doi:10.1038/s41551-021-00805-x

127. Sheng W, LaFleur MW, Nguyen TH, Chen S, Chakravarthy A, Conway JR, et al. LSD1 ablation stimulates anti-tumor immunity and enables checkpoint blockade. Cell. 2018;174(3):549-563.e19. doi:10.1016/j.cell.2018.05.052

128. Wu L, Cao J, Cai WL, Lang SM, Horton JR, Jansen DJ, et al. KDM5 histone demethylases repress immune response via suppression of STING. PLoS Biol. 2018;16(8):e2006134. doi:10.1371/journal.pbio.2006134

129. Chen Q, Zhuang S, Hong Y, Yang L, Guo P, Mo P, et al. Demethylase JMJD2D induces PD-L1 expression to promote colorectal cancer immune escape by enhancing IFNGR1-STAT3-IRF1 signaling. Oncogene. 2022;41(10):1421-1433. doi:10.1038/s41388-021-02173-x

130. Rasmussen PB, Staller P. The KDM5 family of histone demethylases as targets in oncology drug discovery. Epigenomics. 2014;6(3):277-286. doi:10.2217/epi.14.14

131. Jie X, Chen Y, Zhao Y, Yang X, Xu Y, Wang J, et al. Targeting KDM4C enhances CD8+ T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer. J Immunother Cancer. 2022;10(2):e003716. doi:10.1136/jitc-2021-003716

132. Nagarsheth N, Peng D, Kryczek I, Wu K, Li W, Zhao E, et al. PRC2 epigenetically silences Th1-type chemokines to suppress effector T-cell trafficking in colon cancer. Cancer Res. 2016;76(2):275-282. doi:10.1158/0008-5472.can-15-1938

133. Zhang M, Liu Y, Hou S, Wang Y, Wang C, Yin Y, et al. KDM4B, a potential prognostic biomarker revealed by large-scale public databases and clinical samples in uterine corpus endometrial carcinoma. Mol Omics. 2022;18(5):506-519. doi:10.1039/d1mo00287b

134. Sheng W, Liu Y, Chakraborty D, Debo B, Shi Y. Simultaneous inhibition of LSD1 and TGFβ enables eradication of poorly immunogenic tumors with anti-PD-1 treatment. Cancer Discov. 2021;11(8):1970-1981. doi:10.1158/2159-8290.cd-20-0017

135. Zhong C, Tao B, Li X, Xiang W, Peng L, Peng T, et al. HOXA-AS2 contributes to regulatory T cell proliferation and immune tolerance in glioma through the miR-302a/KDM2A/JAG1 axis. Cell Death Dis. 2022;13(2):160. doi:10.1038/s41419-021-04471-4

136. Perillo NL, Pace KE, Seilhamer JJ, Baum LG. Apoptosis of T cells mediated by galectin-1. Nature. 1995;378(6558):736-739. doi:10.1038/378736a0

137. Motz GT, Santoro SP, Wang L-P, Garrabrant T, Lastra RR, Hagemann IS, et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat Med. 2014;20(6):607-615. doi:10.1038/nm.3541

138. Demaria O, De Gassart A, Coso S, Gestermann N, Di Domizio J, Flatz L, et al. STING activation of tumor endothelial cells initiates spontaneous and therapeutic antitumor immunity. Proc Natl Acad Sci U S A. 2015;112(50):15408-15413. doi:10.1073/pnas.1512832112

139. Tan J, Fan W, Liu T, Zhu B, Liu Y, Wang S, et al. TREM2+ macrophages suppress CD8+ T-cell infiltration after transarterial chemoembolisation in hepatocellular carcinoma. J Hepatol. 2023;79(1):126-140. doi:10.1016/j.jhep.2023.02.032

140. Nambiar DK, Aguilera T, Cao H, Kwok S, Kong C, Bloomstein J, et al. Galectin-1-driven T cell exclusion in the tumor endothelium promotes immunotherapy resistance. J Clin Invest. 2019;129(12):5553-5567. doi:10.1172/jci129025

141. Ziogas AC, Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Terpos E, et al. VEGF directly suppresses activation of T cells from ovarian cancer patients and healthy individuals via VEGF receptor type 2. Int J Cancer. 2012;130(4):857-864. doi:10.1002/ijc.26094

142. Gavalas NG, Tsiatas M, Tsitsilonis O, Politi E, Ioannou K, Ziogas AC, et al. VEGF directly suppresses activation of T cells from ascites secondary to ovarian cancer via VEGF receptor type 2. Br J Cancer. 2012;107(11):1869-1875. doi:10.1038/bjc.2012.468

143. Meder L, Schuldt P, Thelen M, Schmitt A, Dietlein F, Klein S, et al. Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer. Cancer Res. 2018;78(15):4270-4281. doi:10.1158/0008-5472.can-17-2176

144. Voron T, Colussi O, Marcheteau E, Pernot S, Nizard M, Pointet AL, et al. VEGF-A modulates expression of inhibitory checkpoints on CD8+ T cells in tumors. J Exp Med. 2015;212(2):139-148. doi:10.1084/jem.20140559

145. Kuo PL, Huang MS, Hung JY, Chou SH, Chiang SY, Huang YF, et al. Synergistic effect of lung tumor-associated dendritic cell-derived HB-EGF and CXCL5 on cancer progression. Int J Cancer. 2014;135(1):96-108. doi:10.1002/ijc.28673

146. Li C, Fu C, Zhou W, Li H, Liu Z, Wu G, et al. Lactylation modification of HIF-1α enhances its stability by blocking VHL recognition. Cell Commun Signal. 2025;23(1):364. doi:10.1186/s12964-025-02366-x

147. Wang X, Li Y, Tang Y, Liu Z, Liu Y, Fu X, et al. PD-L1 delactylation-promoted nuclear translocation accelerates liver cancer growth through elevating SQLE transcription activity. Cancer Lett. 2025;630:217901. doi:10.1016/j.canlet.2025.217901

148. Han H, Wang S, Ma L, Yin H, Cheng X, Wang Y, et al. ASH2L-K312-Lac stimulates angiogenesis in tumors to expedite the malignant progression of hepatocellular carcinoma. Adv Sci (Weinh). 2025;12(40):e09477. doi:10.1002/advs.202509477

149. Heintzman DR, Fisher EL, Rathmell JC. Microenvironmental influences on T cell immunity in cancer and inflammation. Cell Mol Immunol. 2022;19(3):316-326. doi:10.1038/s41423-021-00833-2

150. Cheng J, Yan J, Liu Y, Shi J, Wang H, Zhou H, et al. Cancer-cell-derived fumarate suppresses the anti-tumor capacity of CD8+ T cells in the tumor microenvironment. Cell Metab. 2023;35(6):961-978.e10. doi:10.1016/j.cmet.2023.04.017

151. Wen Y, Hou Y, Yi X, Sun S, Guo J, He X, et al. EZH2 activates CHK1 signaling to promote ovarian cancer chemoresistance by maintaining the properties of cancer stem cells. Theranostics. 2021;11(4):1795-1813. doi:10.7150/thno.48101

152. Du W, Xia X, Hu F, Yu J. Extracellular matrix remodeling in the tumor immunity. Front Immunol. 2023;14:1340634. doi:10.3389/fimmu.2023.1340634

153. Prakash J, Shaked Y. The interplay between extracellular matrix remodeling and cancer therapeutics. Cancer Discov. 2024;14(8):1375-1388. doi:10.1158/2159-8290.cd-24-0002

154. Mai Z, Lin Y, Lin P, Zhao X, Cui L. Modulating extracellular matrix stiffness: a strategic approach to boost cancer immunotherapy. Cell Death Dis. 2024;15(5):307. doi:10.1038/s41419-024-06697-4

155. Peng DH, Rodriguez BL, Diao L, Chen L, Wang J, Byers LA, et al. Collagen promotes anti-PD-1/PD-L1 resistance in cancer through LAIR1-dependent CD8+ T cell exhaustion. Nat Commun. 2020;11(1):4520. doi:10.1038/s41467-020-18298-8

156. Sun X, Wu B, Chiang HC, Deng H, Zhang X, Xiong W, et al. Tumour DDR1 promotes collagen fibre alignment to instigate immune exclusion. Nature. 2021;599(7886):673-678. doi:10.1038/s41586-021-04057-2

157. Chen Z, Han F, Du Y, Shi H, Zhou W. Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions. Signal Transduct Target Ther. 2023;8(1):70. doi:10.1038/s41392-023-01332-8

158. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285(21):1182-1186. doi:10.1056/nejm197111182852108

159. Ribatti D. Judah Folkman, a pioneer in the study of angiogenesis. Angiogenesis. 2008;11(1):3-10. doi:10.1007/s10456-008-9092-6

160. Patel SA, Nilsson MB, Le X, Cascone T, Jain RK, Heymach JV. Molecular mechanisms and future implications of VEGF/VEGFR in cancer therapy. Clin Cancer Res. 2023;29(1):30-39. doi:10.1158/1078-0432.ccr-22-1366

161. Rak J, Mitsuhashi Y, Bayko L, Filmus J, Shirasawa S, Sasazuki T, et al. Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. Cancer Res. 1995;55(20):4575-4580. PMID:7553632

162. Nilsson MB, Zage PE, Zeng L, Xu L, Cascone T, Wu HK, et al. Multiple receptor tyrosine kinases regulate HIF-1alpha and HIF-2alpha in normoxia and hypoxia in neuroblastoma: implications for antiangiogenic mechanisms of multikinase inhibitors. Oncogene. 2010;29(20):2938-2949. doi:10.1038/onc.2010.60

163. Nilsson MB, Robichaux J, Herynk MH, Cascone T, Le X, Elamin Y, et al. Altered regulation of HIF-1α in naive- and drug-resistant EGFR-mutant NSCLC: implications for a vascular endothelial growth factor-dependent phenotype. J Thorac Oncol. 2021;16(3):439-451. doi:10.1016/j.jtho.2020.11.022

164. Allen E, Jabouille A, Rivera LB, Lodewijckx I, Missiaen R, Steri V, et al. Combined antiangiogenic and anti-PD-L1 therapy stimulates tumor immunity through HEV formation. Sci Transl Med. 2017;9(385):eaak9679. doi:10.1126/scitranslmed.aak9679

165. Lee WS, Yang H, Chon HJ, 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. doi:10.1038/s12276-020-00500-y

166. Kim CG, Jang M, Kim Y, Leem G, Kim KH, Lee H, et al. VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers. Sci Immunol. 2019;4(41):eaay0555. doi:10.1126/sciimmunol.aay0555

167. Mo CK, Liu J, Chen S, Storrs E, Targino da Costa ALN, Houston A, et al. Tumour evolution and microenvironment interactions in 2D and 3D space. Nature. 2024;634(8036):1178-1186. doi:10.1038/s41586-024-08087-4

168. Xiao J, Yu X, Meng F, Zhang Y, Zhou W, Ren Y, et al. Integrating spatial and single-cell transcriptomics reveals tumor heterogeneity and intercellular networks in colorectal cancer. Cell Death Dis. 2024;15(5):326. doi:10.1038/s41419-024-06598-6

169. Xie L, Kong H, Yu J, Sun M, Lu S, Zhang Y, et al. Spatial transcriptomics reveals heterogeneity of histological subtypes between lepidic and acinar lung adenocarcinoma. Clin Transl Med. 2024;14(2):e1573. doi:10.1002/ctm2.1573

170. Tavernari D, Battistello E, Dheilly E, Petruzzella AS, Mina M, Sordet-Dessimoz J, et al. Nongenetic evolution drives lung adenocarcinoma spatial heterogeneity and progression. Cancer Discov. 2021;11(6):1490-1507. doi:10.1158/2159-8290.cd-20-1274

171. Xiong X, Zheng LW, Ding Y, Chen YF, Cai YW, Wang LP, et al. Breast cancer: pathogenesis and treatments. Signal Transduct Target Ther. 2025;10(1):49. doi:10.1038/s41392-024-02108-4

172. Wu L, Yan J, Bai Y, Chen F, Zou X, Xu J, et al. An invasive zone in human liver cancer identified by Stereo-seq promotes hepatocyte-tumor cell crosstalk, local immunosuppression and tumor progression. Cell Res. 2023;33(7):585-603. doi:10.1038/s41422-023-00831-1

173. Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19(6):307-325. doi:10.1038/s41568-019-0144-6

174. Schumacher TN, Thommen DS. Tertiary lymphoid structures in cancer. Science. 2022;375(6576):eabf9419. doi:10.1126/science.abf9419

175. Cheng R, Li S, Ma X, Zhuang W, Lei Y, He J, et al. Intratumoral antigen-presenting cell activation by a nanovesicle for the concurrent tertiary lymphoid structure de novo neogenesis. Sci Adv. 2025;11(8):eadr1299. doi:10.1126/sciadv.adr1299

176. Gao X, Zhao X, Li X, Zhang J, Zhao H, Ma Y. Editorial: Tertiary lymphoid structures (TLS) in the tumor immune microenvironment. Front Immunol. 2025;16:1555677. doi:10.3389/fimmu.2025.1555677

177. Lu Y, Zhao Q, Liao JY, Song E, Xia Q, Pan J, et al. Complement signals determine opposite effects of B cells in chemotherapy-induced immunity. Cell. 2020;180(6):1081-1097.e24. doi:10.1016/j.cell.2020.02.015

178. Lee-Chang C, Miska J, Hou D, Rashidi A, Zhang P, Burga RA, et al. Activation of 4-1BBL+ B cells with CD40 agonism and IFNγ elicits potent immunity against glioblastoma. J Exp Med. 2021;218(1):e20200913. doi:10.1084/jem.20200913

179. Chisca M, Choutka C, Kassiotis G. Immunogenicity of endogenous retroviruses in health and disease. Immunol Rev. 2024;317(1):168-189. doi:10.1111/imr.13378

180. Bruno TC, Ebner PJ, Moore BL, Squalls OG, Waugh KA, Eruslanov EB, et al. Antigen-presenting intratumoral B cells affect CD4+ TIL phenotypes in non-small cell lung cancer patients. Cancer Immunol Res. 2017;5(10):898-907. doi:10.1158/2326-6066.cir-17-0075

181. Ma K, Wang L, Li W, Tang T, Ma B, Zhang L, et al. Turning cold into hot: emerging strategies to fire up the tumor microenvironment. Trends Cancer. 2025;11(2):117-134. doi:10.1016/j.trecan.2024.11.011

182. Xiao C, Xiong W, Xu Y, Zou J, Zeng Y, Liu J, et al. Immunometabolism: a new dimension in immunotherapy resistance. Front Med (Lausanne). 2023;17(4):585-616. doi:10.1007/s11684-023-1012-z

183. Almawash S. Revolutionary cancer therapy for personalization and improved efficacy: strategies to overcome resistance to immune checkpoint inhibitor therapy. Cancers (Basel). 2025;17(5):880. doi:10.3390/cancers17050880

184. You Q, Wu G, Li H, Liu J, Cao F, Ding L, et al. A nanovaccine targeting cancer stem cells and bulk cancer cells for postoperative cancer immunotherapy. Nat Nanotechnol. 2025;20(8):1298-1311. doi:10.1038/s41565-025-01952-x

185. Zhao X, Qin X, Wang R, Wang Y, He Y, Wang Y, et al. An epigenetic nanoagonist facilitates T cell priming, recruitment, and reinvigoration in tumors resistant to PD-L1 therapy. Adv Mater. 2025;37(45):e02800. doi:10.1002/adma.202502800

186. Qian ZY, Pan YQ, Li XX, Chen YX, Wu HX, Liu ZX, et al. Modulator of TMB-associated immune infiltration (MOTIF) predicts immunotherapy response and guides combination therapy. Sci Bull (Beijing). 2024;69(6):803-822. doi:10.1016/j.scib.2024.01.025

187. Shorer O, Pinhasi A, Yizhak K. Single-cell meta-analysis of T cells reveals clonal dynamics of response to checkpoint immunotherapy. Cell Genom. 2025;5(5):100842. doi:10.1016/j.xgen.2025.100842