Tumor Metastasis: Mechanistic Insights and Therapeutic Intervention

Abstract

Metastasis remains a leading cause of cancer-related deaths, defined by a complex, multi-step process in which tumor cells spread and form secondary growths in distant tissues. Despite substantial progress in understanding metastasis, the molecular mechanisms driving this process and the development of effective therapies remain incompletely understood. Elucidating the molecular pathways governing metastasis is essential for the discovery of innovative therapeutic targets. The rapid advancements in sequencing technologies and the expansion of biological databases have significantly deepened our understanding of the molecular drivers of metastasis and associated drug resistance. This review focuses on the molecular drivers of metastasis, particularly the roles of genetic mutations, epigenetic changes, and post-translational modifications in metastasis progression. We also examine how the tumor microenvironment influences metastatic behavior and explore emerging therapeutic strategies, including targeted therapies and immunotherapies. Finally, we discuss future research directions, stressing the importance of novel treatment approaches and personalized strategies to overcome metastasis and improve patient outcomes. By integrating contemporary insights into the molecular basis of metastasis and therapeutic innovation, this review provides a comprehensive framework to guide future research and clinical advancements in metastatic cancer.

Keywords

epigenomics / therapy / tumor metastasis / tumor microenvironment

References

[1] I. J.Fidler, “The Pathogenesis of Cancer Metastasis: The ‘Seed and Soil’ Hypothesis Revisited,” Nature Reviews Cancer 3, no. 6 (2003):453–458.

[2] J.Massagué and K. Ganesh, “Metastasis-Initiating Cellbys and Ecosystems,” Cancer Discovery 11, no. 4 (2021):971–994.

[3] E.Batlle and H.Clevers, “Cancer Stem Cells Revisited,” Nature Medicine 23, no. 10 (2017):1124–1134.

[4] A. CChiang and J.Massagué, “Molecular Basis of Metastasis,” New England Journal of Medicine 359, no. 26 (2008):2814–2823.

[5] J. J. FSleeboom, G. S. van Tienderen, K.Schenke-Layland, L. J. W.van der Laan, A. A.Khalil, and M. M. A. Verstegen, “The Extracellular Matrix as Hallmark of Cancer and Metastasis: From Biomechanics to Therapeutic Targets,” Science Translational Medicine 16, no. 728 (2024):eadg3840.

[6] Y.Jiang, H.Zhang, J.Wang, Y. Liu, T.Luo, and H.Hua, “Targeting Extracellular Matrix Stiffness and Mechanotransducers to Improve Cancer Therapy,” Journal of Hematology &Oncology 15, no. 1 (2022):34.

[7] Z.Huang, Z.Zhang, C.Zhou, L. Liu, and C.Huang, “Epithelial–Mesenchymal Transition: The History, Regulatory Mechanism, and Cancer Therapeutic Opportunities,” MedComm 3, no. 2 (2022):e144.

[8] Z.Wang, N.Zhang, M.Zhang, et al., “GTP Cyclohydrolase Drives Breast Cancer Development and Promotes EMT in an Enzyme-Independent Manner,” Cancer Research 83, no. 20 (2023):3400–3413.

[9] F.Shu, H.Liu, X.Chen, et al., “m6A Modification Promotes EMT and Metastasis of Castration-Resistant Prostate Cancer by Upregulating NFIB,” Cancer Research 84, no. 12 (2024):1947–1962.

[10] L.Wang, S.Li, H.Luo, Q. Lu, and S.Yu, “PCSK9 Promotes the Progression and Metastasis of Colon Cancer Cells Through Regulation of EMT and PI3K/AKT Signaling in Tumor Cells and Phenotypic Polarization of Macrophages,” Journal of Experimental &Clinical Cancer Research 41, no. 1 (2022):303.

[11] L.Chen, S.Zhu, T.Liu, et al., “Aberrant Epithelial Cell Interaction Promotes Esophageal Squamous-Cell Carcinoma Development and Progression,” Signal Transduction and Targeted Therapy 8, no. 1 (2023):453.

[12] C.Song and C.Zhou, “HOXA10 Mediates Epithelial–Mesenchymal Transition to Promote Gastric Cancer Metastasis Partly via Modulation of TGFB2/Smad/METTL3 Signaling Axis,” Journal of Experimental &Clinical Cancer Research 40, no. 1 (2021):62.

[13] X.Tan, G. Y.Xiao, S.Wang, et al., “EMT-Activated Secretory and Endocytic Vesicular Trafficking Programs Underlie a Vulnerability to PI4K2A Antagonism in Lung Cancer,” Journal of Clinical Investigation 133, no. 7 (2023):e165863.

[14] A. WLambert and R. A. Weinberg, “Linking EMT Programmes to Normal and Neoplastic Epithelial Stem Cells,” Nature Reviews Cancer 21, no. 5 (2021):325–338.

[15] I.Pastushenko and C.Blanpain, “EMT Transition States During Tumor Progression and Metastasis,” Trends in Cell Biology 29, no. 3 (2019):212–226.

[16] R.Fontana, A.Mestre-Farrera, and J.Yang, “Update on Epithelial–Mesenchymal Plasticity in Cancer Progression,” Annual Review of Pathology: Mechanisms of Disease 19 (2024):133–156.

[17] F.Andriani, G.Bertolini, F.Facchinetti, et al., “Conversion to Stem-Cell State in Response to Microenvironmental Cues Is Regulated by Balance Between Epithelial and Mesenchymal Features in Lung Cancer Cells,” Molecular Oncology 10, no. 2 (2016):253–271.

[18] N.Harner-Foreman, J. Vadakekolathu, S. A.Laversin, et al., “A Novel Spontaneous Model of Epithelial–Mesenchymal Transition (EMT) Using a Primary Prostate Cancer Derived Cell Line Demonstrating Distinct Stem-Like Characteristics,” Scientific Reports 7 (2017):40633.

[19] B.Bierie, S. E.Pierce, C.Kroeger, et al., “Integrin-β4 Identifies Cancer Stem Cell-Enriched Populations of Partially Mesenchymal Carcinoma Cells,” Proceedings of the National Academy of Sciences 114, no. 12 (2017): E2337–E2346.

[20] A.Vasseur, N.Kiavue, F. C.Bidard, J. Y.Pierga, and L.Cabel, “Clinical Utility of Circulating Tumor Cells: An Update,” Molecular Oncology 15, no. 6 (2021):1647–1666.

[21] Z.Ye, Y.Ding, Z.Chen, et al., “Detecting and Phenotyping of Aneuploid Circulating Tumor Cells in Patients With Various Malignancies,” Cancer Biology &Therapy 20, no. 4 (2019):546–551.

[22] L.Ren, X.Zhong, W.Liu, et al., “Clinical Significance of a Circulating Tumor Cell-Based Classifier in Stage IB Lung Adenocarcinoma: A Multicenter, Cohort Study,” Annals of Surgery 277, no. 2 (2023): e439–e448.

[23] M.Bates, B. M.Mohamed, M. P.Ward, et al., “Circulating Tumour Cells: The Good, the Bad and the Ugly,” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1878, no. 2 (2023):188863.

[24] A.Ring, B. D.Nguyen-Sträuli, A.Wicki, and N.Aceto, “Biology, Vulnerabilities and Clinical Applications of Circulating Tumour Cells,” Nature Reviews Cancer 23, no. 2 (2023):95–111.

[25] Z.Diamantopoulou, F. Castro-Giner, F. D.Schwab, et al., “The Metastatic Spread of Breast Cancer Accelerates During Sleep,” Nature 607, no. 7917 (2022):156–162.

[26] S.Amintas, A.Bedel, F.Moreau-Gaudry, et al., “Circulating Tumor Cell Clusters: United We Stand Divided We Fall,” International Journal of Molecular Sciences 21, no. 7 (2020):2653.

[27] E.Piskounova, M.Agathocleous, M. M.Murphy, et al., “Oxidative Stress Inhibits Distant Metastasis by Human Melanoma Cells,” Nature 527, no. 7577 (2015):186–191.

[28] Q.Zhan, B.Liu, X.Situ, et al., “New Insights Into the Correlations Between Circulating Tumor Cells and Target Organ Metastasis,” Signal Transduction and Targeted Therapy 8, no. 1 (2023):465.

[29] D.Lin, L.Shen, M.Luo, et al., “Circulating Tumor Cells: Biology and Clinical Significance,” Signal Transduction and Targeted Therapy 6, no. 1 (2021):404.

[30] K.Pantel and M. R. Speicher, “The Biology of Circulating Tumor Cells,” Oncogene 35, no. 10 (2016):1216–1224.

[31] S.Duan, S.Nordmeier, A. E.Byrnes, and I. L. O.Buxton, “Extracellular Vesicle-Mediated Purinergic Signaling Contributes to Host Microenvironment Plasticity and Metastasis in Triple Negative Breast Cancer,” International Journal of Molecular Sciences 22, no. 2 (2021):597.

[32] H.Zheng, M.An, Y.Luo, et al., “PDGFRalpha(+)ITGA11(+) Fibroblasts Foster Early-Stage Cancer Lymphovascular Invasion and Lymphatic Metastasis via ITGA11-SELE Interplay,” Cancer Cell 42, no. 4 (2024):682–700 e12.

[33] X.Liu, J.Song, H.Zhang, et al., “Immune Checkpoint HLA-E:CD94-NKG2A Mediates Evasion of Circulating Tumor Cells From NK Cell Surveillance,” Cancer Cell 41, no. 2 (2023):272–287.

[34] M.Esposito, N.Mondal, T. M.Greco, et al., “Bone Vascular Niche E-Selectin Induces Mesenchymal-Epithelial Transition and Wnt Activation in Cancer Cells to Promote Bone Metastasis,” Nature Cell Biology 21, no. 5 (2019):627–639.

[35] J.Cui, C.Zhang, J. E.Lee, et al., “MLL3 Loss Drives Metastasis by Promoting a Hybrid Epithelial–Mesenchymal Transition State,” Nature Cell Biology 25, no. 1 (2023):145–158.

[36] J.Xia, S.Ma, X.Zhu, et al., “Versatile Ginsenoside Rg3 Liposomes Inhibit Tumor Metastasis by Capturing Circulating Tumor Cells and Destroying Metastatic Niches,” Science Advances 8, no. 6 (2022):eabj1262.

[37] M.Ito, Y.Horimoto, E.Tokuda, et al., “Impact of Circulating Tumour Cells on Survival of Eribulin-Treated Patients With Metastatic Breast Cancer,” Medical Oncology 36, no. 10 (2019):89.

[38] A. CObenauf and J.Massagué, “Surviving at a Distance: Organ-Specific Metastasis,” Trends in Cancer 1, no. 1 (2015):76–91.

[39] S.Gerstberger, Q.Jiang, and K.Ganesh, “Metastasis,” Cell 186, no. 8 (2023):1564–1579.

[40] A. W.Lambert, D. R.Pattabiraman, and R. A.Weinberg, “Emerging Biological Principles of Metastasis,” Cell 168, no. 4 (2017):670–691.

[41] E.Risson, A. R.Nobre, V.Maguer-Satta, and J. A.Aguirre-Ghiso, “The Current Paradigm and Challenges Ahead for the Dormancy of Disseminated Tumor Cells,” Nature Cancer 1, no. 7 (2020):672–680.

[42] S.Turajlic and C.Swanton, “Metastasis as an Evolutionary Process,” Science 352, no. 6282 (2016):169–175.

[43] K. W.Hunter, R.Amin, S.Deasy, N. H. Ha, and L.Wakefield, “Genetic Insights Into the Morass of Metastatic Heterogeneity,” Nature Reviews Cancer 18, no. 4 (2018):211–223.

[44] A. W.Lambert, Y.Zhang, and R. A.Weinberg, “Cell-Intrinsic and Microenvironmental Determinants of Metastatic Colonization,” Nature Cell Biology 26, no. 5 (2024):687–697.

[45] J.Urosevic, X.Garcia-Albéniz, E.Planet, et al., “Colon Cancer Cells Colonize the Lung From Established Liver Metastases Through p38 MAPK Signalling and PTHLH,” Nature Cell Biology 16, no. 7 (2014):685–694.

[46] W. W.Xu, B.Li, X. Y.Guan, et al., “Cancer Cell-Secreted IGF2 Instigates Fibroblasts and Bone Marrow-Derived Vascular Progenitor Cells to Promote Cancer Progression,” Nature Communications 8 (2017):14399.

[47] S.Tian, Y.Chu, J.Hu, et al., “Tumour-Associated Neutrophils Secrete AGR2 to Promote Colorectal Cancer Metastasis via Its Receptor Cd98hc-xCT,” Gut 71, no. 12 (2022):2489–2501.

[48] J. L.Liu, X.Xu, Y.Rixiati, et al., “Dysfunctional Circadian Clock Accelerates Cancer Metastasis by Intestinal Microbiota Triggering Accumulation of Myeloid-Derived Suppressor Cells,” Cell Metabolism 36, no. 6 (2024):1320–1334

[49] F.Martínez-Jiménez, P.Priestley, C.Shale, J.Baber, E. Rozemuller, and E.Cuppen, “Genetic Immune Escape Landscape in Primary and Metastatic Cancer,” Nature Genetics 55, no. 5 (2023):820–831.

[50] Y.Sun, P.Wu, Z.Zhang, et al., “Integrated Multi-Omics Profiling to Dissect the Spatiotemporal Evolution of Metastatic Hepatocellular Carcinoma,” Cancer Cell 42, no. 1 (2024):135–156

[51] P.Gui and T. G. Bivona, “Evolution of Metastasis: New Tools and Insights,” Trends in Cancer 8, no. 2 (2022):98–109.

[52] J. JLoh and S.Ma, “Hallmarks of Cancer Stemness,” Cell Stem Cell 31, no. 5 (2024):617–639.

[53] N. JBirkbak and N.McGranahan, “Cancer Genome Evolutionary Trajectories in Metastasis,” Cancer Cell 37, no. 1 (2020):8–19.

[54] Q.Shi, K.Shao, H.Jia, et al., “Genomic Alterations and Evolution of Cell Clusters in Metastatic Invasive Micropapillary Carcinoma of the Breast,” Nature Communications 13, no. 1 (2022):111.

[55] C.Scheel, T.Onder, A.Karnoub, and R. A. Weinberg, “Adaptation Versus Selection: The Origins of Metastatic Behavior,” Cancer Research 67, no. 24 (2007):11476–11480.

[56] C. A.Klein, “Parallel Progression of Primary Tumours and Metastases,” Nature Reviews Cancer 9, no. 4 (2009):302–312.

[57] X.Wang, H.Bai, J.Zhang, et al., “Genetic Intratumor Heterogeneity Remodels the Immune Microenvironment and Induces Immune Evasion in Brain Metastasis of Lung Cancer,” Journal of Thoracic Oncology 19, no. 2 (2024):252–272.

[58] X.Fu, Y.Zhao, J. I.Lopez, et al., “Spatial Patterns of Tumour Growth Impact Clonal Diversification in a Computational Model and the TRACERx Renal Study,” Nature Ecology &Evolution 6, no. 1 (2022):88–102.

[59] J.Li, M. J.Hubisz, E. M.Earlie, et al., “Non-Cell-Autonomous Cancer Progression From Chromosomal Instability,” Nature 620, no. 7976 (2023):1080–1088.

[60] S. F.Bakhoum, B.Ngo, A. M.Laughney, et al., “Chromosomal Instability Drives Metastasis Through a Cytosolic DNA Response,” Nature 553, no. 7689 (2018):467–472.

[61] B.Nguyen, C.Fong, A.Luthra, et al., “Genomic Characterization of Metastatic Patterns From Prospective Clinical Sequencing of 25, 000 Patients,” Cell 185, no. 3 (2022):563–575.

[62] J.Li, M. A.Duran, N.Dhanota, et al., “Metastasis and Immune Evasion From Extracellular cGAMP Hydrolysis,” Cancer Discovery 11, no. 5 (2021):1212–1227.

[63] R.Banerjee, J.Smith, M. R.Eccles, R. J. Weeks, and A.Chatterjee, “Epigenetic Basis and Targeting of Cancer Metastasis,” Trends in Cancer 8, no. 3 (2022):226–241.

[64] Y.Han, D.Wang, L.Peng, et al., “Single-Cell Sequencing: A Promising Approach for Uncovering the Mechanisms of Tumor Metastasis,” Journal of Hematology &Oncology 15, no. 1 (2022):59.

[65] Y.Wu, S.Chen, Y.Shao, et al., “KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer,” Advanced Science 10, no. 31 (2023):e2304638.

[66] C.Guo, A.Sharp, B.Gurel, et al., “Targeting Myeloid Chemotaxis to Reverse Prostate Cancer Therapy Resistance,” Nature 623, no. 7989 (2023):1053–1061.

[67] A.Llorente, M. T.Blasco, I.Espuny, et al., “MAF Amplification Licenses ERαThrough Epigenetic Remodelling to Drive Breast Cancer Metastasis,” Nature Cell Biology 25, no. 12 (2023):1833–1847.

[68] B. GWilson and C. W. M. Roberts, “SWI/SNF Nucleosome Remodellers and Cancer,” Nature Reviews Cancer 11, no. 7 (2011):481–492.

[69] S.Eustermann, A. B.Patel, K. P.Hopfner, Y.He, and P.Korber, “Energy-Driven Genome Regulation by ATP-Dependent Chromatin Remodellers,” Nature Reviews Molecular Cell Biology 25, no. 4 (2024):309–332.

[70] B. J. EMartin, E. F.Ablondi, C.Goglia, C. A.Mimoso, P. REspinel-Cabrera, and K.Adelman, “Global Identification of SWI/SNF Targets Reveals Compensation by EP400,” Cell 186, no. 24 (2023):5290–5307.

[71] B.Ren, J.Yang, C.Wang, et al., “High-Resolution Hi-C Maps Highlight Multiscale 3D Epigenome Reprogramming During Pancreatic Cancer Metastasis,” Journal of Hematology &Oncology 14, no. 1 (2021):120.

[72] L.Dong, D.Lu, R.Chen, et al., “Proteogenomic Characterization Identifies Clinically Relevant Subgroups of Intrahepatic Cholangiocarcinoma,” Cancer Cell 40, no. 1 (2022):70–87.

[73] L.Wang, E.Wang, J.Prado Balcazar, et al., “Chromatin Remodeling of Colorectal Cancer Liver Metastasis Is Mediated by an HGF-PU.1-DPP4 Axis,” Advanced Science 8, no. 19 (2021):e2004673.

[74] S. C.Lee, D. W.Adams, J. J.Ipsaro, et al., “Chromatin Remodeling of Histone H3 Variants by DDM1 Underlies Epigenetic Inheritance of DNA Methylation,” Cell 186, no. 19 (2023):4100–4116.

[75] V.Brower, “Epigenetics: Unravelling the Cancer Code,” Nature 471, no. 7339 (2011):S12–S13.

[76] T.Ushijima, S. J.Clark, and P.Tan, “Mapping Genomic and Epigenomic Evolution in Cancer Ecosystems,” Science 373, no. 6562 (2021):1474–1479.

[77] J. FChen and Q.Yan, “The Roles of Epigenetics in Cancer Progression and Metastasis,” Biochemical Journal 478, no. 17 (2021):3373–3393.

[78] L.Ma, C.Li, H.Yin, et al., “The Mechanism of DNA Methylation and miRNA in Breast Cancer,” International Journal of Molecular Sciences 24, no. 11 (2023):9360.

[79] P.Khan, J. A.Siddiqui, S. K.Maurya, et al., “Epigenetic Landscape of Small Cell Lung Cancer: Small Image of a Giant Recalcitrant Disease,” Seminars in Cancer Biology 83 (2022):57–76.

[80] X.Pan, J.Zhou, Q.Xiao, et al., “Cancer-Associated Fibroblast Heterogeneity Is Associated With Organ-Specific Metastasis in Pancreatic Ductal Adenocarcinoma,” Journal of Hematology &Oncology 14, no. 1 (2021):184.

[81] A. K.Suwala, D.Stichel, D.Schrimpf, et al., “Glioblastomas With Primitive Neuronal Component Harbor a Distinct Methylation and Copy-Number Profile With Inactivation of TP53, PTEN, and RB1,” Acta Neuropathologica 142, no. 1 (2021):179–189.

[82] H.Jung, H. S.Kim, J. Y.Kim, et al., “DNA Methylation Loss Promotes Immune Evasion of Tumours With High Mutation and Copy Number Load,” Nature Communications 10, no. 1 (2019):4278.

[83] L.Guo, T.Hong, Y. T.Lee, et al., “Perturbing TET2 Condensation Promotes Aberrant Genome-Wide DNA Methylation and Curtails Leukaemia Cell Growth,” Nature Cell Biology 26, no. 12 (2024):2154–2167.

[84] X.Deng, Y.Qing, D.Horne, H. Huang, and J.Chen, “The Roles and Implications of RNA m(6)A Modification in Cancer,” Nature Reviews Clinical Oncology 20, no. 8 (2023):507–526.

[85] G.Wang, M.Zhang, Y.Zhang, et al., “NAT10-Mediated mRNA N4-Acetylcytidine Modification Promotes Bladder Cancer Progression,” Clinical and Translational Medicine 12, no. 5 (2022):e738.

[86] F.Luo, M.Zhang, B.Sun, et al., “LINC00115 Promotes Chemoresistant Breast Cancer Stem-Like Cell Stemness and Metastasis Through SETDB1/PLK3/HIF1αSignaling,” Molecular Cancer 23, no. 1 (2024):60.

[87] A.Chen, V. X.Zhang, Q.Zhang, et al., “Targeting the Oncogenic m6A Demethylase FTO Suppresses Tumourigenesis and Potentiates Immune Response in Hepatocellular Carcinoma,” Gut 74, no. 1 (2024):90–102.

[88] M.Han, H.Sun, Q.Zhou, et al., “Effects of RNA Methylation on Tumor Angiogenesis and Cancer Progression,” Molecular Cancer 22, no. 1 (2023):198.

[89] A.Chamorro-Jorganes, W. K. Sweaad, R.Katare, et al., “METTL3 Regulates Angiogenesis by Modulating let-7e-5p and miRNA-18a-5p Expression in Endothelial Cells,” Arteriosclerosis, Thrombosis, and Vascular Biology 41, no. 6 (2021): e325–e337.

[90] K. J.Li, Y.Hong, Y. Z.Yu, et al., “NAT10 Promotes Prostate Cancer Growth and Metastasis by Acetylating mRNAs of HMGA1 and KRT8,” Advanced Science 11, no. 32 (2024):e2310131.

[91] D.Arango, D.Sturgill, N.Alhusaini, et al., “Acetylation of Cytidine in mRNA Promotes Translation Efficiency,” Cell 175, no. 7 (2018):1872–1886.

[92] H.Liu, L.Xu, S.Yue, et al., “Targeting N4-Acetylcytidine Suppresses Hepatocellular Carcinoma Progression by Repressing eEF2-Mediated HMGB2 mRNA Translation,” Cancer Communications 44, no. 9 (2024):1018–1041.

[93] L.Liao, Y.He, S. J.Li, et al., “Lysine 2-Hydroxyisobutyrylation of NAT10 Promotes Cancer Metastasis in an ac4C-Dependent Manner,” Cell Research 33, no. 5 (2023):355–371.

[94] Z.He, Y.Zhong, P.Regmi, et al., “Exosomal Long Non-Coding RNA TRPM2-AS Promotes Angiogenesis in Gallbladder Cancer Through Interacting With PABPC1 to Activate NOTCH1 Signaling Pathway,” Molecular Cancer 23, no. 1 (2024):65.

[95] K.Yuan, J.Lan, L.Xu, et al., “Long Noncoding RNA TLNC1 Promotes the Growth and Metastasis of Liver Cancer via Inhibition of p53 Signaling,” Molecular Cancer 21, no. 1 (2022):105.

[96] Y. L.Liang, Y.Zhang, X. R.Tan, et al., “A lncRNA Signature Associated With Tumor Immune Heterogeneity Predicts Distant Metastasis in Locoregionally Advanced Nasopharyngeal Carcinoma,” Nature Communications 13, no. 1 (2022):2996.

[97] E.Martinez-Terroba, L. M Plasek-Hegde, I.Chiotakakos, et al., “Overexpression of Malat1 Drives Metastasis Through Inflammatory Reprogramming of the Tumor Microenvironment,” Science Immunology 9, no. 96 (2024):eadh5462.

[98] X. R.Hsu, J. E.Wu, Y. Y.Wu, et al., “Exosomal Long Noncoding RNA MLETA1 Promotes Tumor Progression and Metastasis by Regulating the miR-186-5p/EGFR and miR-497-5p/IGF1R Axes in Non-Small Cell Lung Cancer,” Journal of Experimental &Clinical Cancer Research 42, no. 1 (2023):283.

[99] Y.Chen, Z.Li, X.Chen, and S. Zhang, “Long Non-Coding RNAs: From Disease Code to Drug Role,” Acta Pharmaceutica Sinica B 11, no. 2 (2021):340–354.

[100] S.Liu, Y.Wang, T.Wang, et al., “CircPCNXL2 Promotes Tumor Growth and Metastasis by Interacting With STRAP to Regulate ERK Signaling in Intrahepatic Cholangiocarcinoma,” Molecular Cancer 23, no. 1 (2024):35.

[101] Y.Liang, Q.Lu, W.Li, et al., “Reactivation of Tumour Suppressor in Breast Cancer by Enhancer Switching Through NamiRNA Network,” Nucleic Acids Research 49, no. 15 (2021):8556–8572.

[102] C.Lin, M.Ma, Y.Zhang, et al., “The N(6)-methyladenosine Modification of circALG1 Promotes the Metastasis of Colorectal Cancer Mediated by the miR-342-5p/PGF Signalling Pathway,” Molecular Cancer 21, no. 1 (2022):80.

[103] L.Xu, P.Wang, L.Li, et al., “circPSD3 Is a Promising Inhibitor of uPA System to Inhibit Vascular Invasion and Metastasis in Hepatocellular Carcinoma,” Molecular Cancer 22, no. 1 (2023):174.

[104] M. A.Jafri, M. HAl-Qahtani, and J. W.Shay, “Role of miRNAs in Human Cancer Metastasis: Implications for Therapeutic Intervention,” Seminars in Cancer Biology 44 (2017):117–131.

[105] X.Yuan, N.Qian, S.Ling, et al., “Breast Cancer Exosomes Contribute to Pre-Metastatic Niche Formation and Promote Bone Metastasis of Tumor Cells,” Theranostics 11, no. 3 (2021):1429–1445.

[106] Y.Zhao, Y.Jia, J.Wang, et al., “circNOX4 Activates an Inflammatory Fibroblast Niche to Promote Tumor Growth and Metastasis in NSCLC via FAP/IL-6 Axis,” Molecular Cancer 23, no. 1 (2024):47.

[107] G.Jiang, C.Li, M.Lu, K.Lu, and H.Li, “Protein Lysine Crotonylation: Past, Present, Perspective,” Cell Death &Disease 12, no. 7 (2021):703.

[108] R.Kumar, D.Mehta, N.Mishra, D. Nayak, and S.Sunil, “Role of Host-Mediated Post-Translational Modifications (PTMs) in RNA Virus Pathogenesis,” International Journal of Molecular Sciences 22, no. 1 (2020):323.

[109] Y.Geffen, S.Anand, Y.Akiyama, et al., “Pan-Cancer Analysis of Post-Translational Modifications Reveals Shared Patterns of Protein Regulation,” Cell 186, no. 18 (2023):3945–3967.

[110] B. CTaylor and N. L. Young, “Combinations of Histone Post-Translational Modifications,” Biochemical Journal 478, no. 3 (2021):511–532.

[111] K.Adam and T.Hunter, “Histidine Kinases and the Missing Phosphoproteome From Prokaryotes to Eukaryotes,” Laboratory Investigation 98, no. 2 (2018):233–247.

[112] F.Keck, P.Ataey, M.Amaya, C. Bailey, and A.Narayanan, “Phosphorylation of Single Stranded RNA Virus Proteins and Potential for Novel Therapeutic Strategies,” Viruses 7, no. 10 (2015):5257–5273.

[113] Y.Zhang, M.Zhao, H.Gao, et al., “MAPK Signalling-Induced Phosphorylation and Subcellular Translocation of PDHE1αPromotes Tumour Immune Evasion,” Nature Metabolism 4, no. 3 (2022):374–388.

[114] V.Singh, M.Ram, R.Kumar, R. Prasad, B. K.Roy, and K. K.Singh, “Phosphorylation: Implications in Cancer,” Protein Journal 36, no. 1 (2017):1–6.

[115] S.Wang, G.Mu, B.Qiu, et al., “The Function and Related Diseases of Protein Crotonylation,” International Journal of Biological Sciences 17, no. 13 (2021):3441–3455.

[116] T.Baldensperger and M. A. Glomb, “Pathways of Non-Enzymatic Lysine Acylation,” Frontiers in Cell and Developmental Biology 9 (2021):664553.

[117] M.Shvedunova and A.Akhtar, “Modulation of Cellular Processes by Histone and Non-Histone Protein Acetylation,” Nature Reviews Molecular Cell Biology 23, no. 5 (2022):329–349.

[118] B. J. EMartin, J.Brind’Amour, A.Kuzmin, et al., “Transcription Shapes Genome-Wide Histone Acetylation Patterns,” Nature Communications 12, no. 1 (2021):210.

[119] J. EAudia and R. M. Campbell, “Histone Modifications and Cancer,” Cold Spring Harbor Perspectives in Biology 8, no. 4 (2016):a019521.

[120] Y.Xu, W.Liao, Q.Luo, D. Yang, and M.Pan, “Histone Acetylation Regulator-Mediated Acetylation Patterns Define Tumor Malignant Pathways and Tumor Microenvironment in Hepatocellular Carcinoma,” Frontiers in Immunology 13 (2022):761046.

[121] X.Zheng, Q.Wang, Y.Zhou, et al., “N-Acetyltransferase 10 Promotes Colon Cancer Progression by Inhibiting Ferroptosis Through N4-Acetylation and Stabilization of Ferroptosis Suppressor Protein 1 (FSP1) mRNA,” Cancer Communications 42, no. 12 (2022):1347–1366.

[122] T.Narita, Y.Higashijima, S.Kilic, T.Liebner, J.Walter, and C.Choudhary, “Acetylation of Histone H2B Marks Active Enhancers and Predicts CBP/p300 Target Genes,” Nature Genetics 55, no. 4 (2023):679–692.

[123] J.Lu, X.He, L.Zhang, R. Zhang, and W.Li, “Acetylation in Tumor Immune Evasion Regulation,” Frontiers in Pharmacology 12 (2021):771588.

[124] L.Yu, L.Dong, H.Li, et al., “Ubiquitination-Mediated Degradation of SIRT1 by SMURF2 Suppresses CRC Cell Proliferation and Tumorigenesis,” Oncogene 39, no. 22 (2020):4450–4464.

[125] F.Hua, W.Hao, L.Wang, and S. Li, “Linear Ubiquitination Mediates EGFR-Induced NF-κB Pathway and Tumor Development,” International Journal of Molecular Sciences 22, no. 21 (2021):11875.

[126] L. D.Cervia, T.Shibue, A. A.Borah, et al., “A Ubiquitination Cascade Regulating the Integrated Stress Response and Survival in Carcinomas,” Cancer Discovery 13, no. 3 (2023):766–795.

[127] M.Zhang, J.Li, S.Liu, F. Zhou, and L.Zhang, “UCHL5 Is a Putative Prognostic Marker in Renal Cell Carcinoma: A Study of UCHL Family,” Molecular Biomedicine 5, no. 1 (2024):28.

[128] D. RSquair and S.Virdee, “A New Dawn Beyond Lysine Ubiquitination,” Nature Chemical Biology 18, no. 8 (2022):802–811.

[129] K. FWitting and M. P. C. Mulder, “Highly Specialized Ubiquitin-Like Modifications: Shedding Light Into the UFM1 Enigma,” Biomolecules 11, no. 2 (2021):255.

[130] F.Thery, L.Martina, C.Asselman, et al., “Ring Finger Protein 213 Assembles Into a Sensor for ISGylated Proteins With Antimicrobial Activity,” Nature Communications 12, no. 1 (2021):5772.

[131] H. G.Han, H. W.Moon, and Y. J.Jeon, “ISG15 in Cancer: Beyond Ubiquitin-Like Protein,” Cancer Letters 438 (2018):52–62.

[132] A. CTecalco-Cruz, G. Velasco-Loyden, L.Robles-Villarruel, et al., “Interferon-Stimulated Gene 15 and ISGylation Are Upregulated in Glioblastoma,” Biochemical and Biophysical Research Communications 621 (2022):144–150.

[133] O.Mirzalieva, M.Juncker, J.Schwartzenburg, and S.Desai, “ISG15 and ISGylation in Human Diseases,” Cells 11, no. 3 (2022):538.

[134] T.Qu, W.Zhang, C.Yan, et al., “ISG15 Targets Glycosylated PD-L1 and Promotes Its Degradation to Enhance Antitumor Immune Effects in Lung Adenocarcinoma,” Journal of Translational Medicine 21, no. 1 (2023):341.

[135] A.Folci, F.Mirabella, and M.Fossati, “Ubiquitin and Ubiquitin-Like Proteins in the Critical Equilibrium Between Synapse Physiology and Intellectual Disability,” eNeuro 7, no. 4 (2020):ENEURO.0137-20.2020.

[136] X.Diao, C.Guo, H.Zheng, et al., “SUMOylation-Triggered Alix Activation Modulates Extracellular Vesicles circTLCD4-RWDD3 to Promote Lymphatic Metastasis of Non-Small Cell Lung Cancer,” Signal Transduction and Targeted Therapy 8, no. 1 (2023):426.

[137] Y.Fan, X.Li, L.Zhang, et al., “SUMOylation in Viral Replication and Antiviral Defense,” Advanced Science 9, no. 7 (2022):e2104126.

[138] J.Li, J. A.Johnson, and H.Su, “Ubiquitin and Ubiquitin-Like Proteins in Cardiac Disease and Protection,” Current Drug Targets 19, no. 9 (2018):989–1002.

[139] P.Gatel, M.Piechaczyk, and G.Bossis, “Ubiquitin, SUMO, and Nedd8 as Therapeutic Targets in Cancer,” Advances in Experimental Medicine and Biology 1233 (2020):29–54.

[140] A.Aichem and M.Groettrup, “The Ubiquitin-Like Modifier FAT10 in Cancer Development,” The International Journal of Biochemistry &Cell Biology 79 (2016):451–461.

[141] H.Su, M.Qin, Q.Liu, B. Jin, X.Shi, and Z.Xiang, “Ubiquitin-Like Protein UBD Promotes Cell Proliferation in Colorectal Cancer by Facilitating p53 Degradation,” Frontiers in Oncology 11 (2021):691347.

[142] S. M.Fendt, C.Frezza, and A.Erez, “Targeting Metabolic Plasticity and Flexibility Dynamics for Cancer Therapy,” Cancer Discovery 10, no. 12 (2020):1797–1807.

[143] F.Yang, L.Hilakivi-Clarke, A.Shaha, et al., “Metabolic Reprogramming and Its Clinical Implication for Liver Cancer,” Hepatology 78, no. 5 (2023):1602–1624.

[144] I.Elia, G.Doglioni, and S. M.Fendt, “Metabolic Hallmarks of Metastasis Formation,” Trends in Cell Biology 28, no. 8 (2018):673–684.

[145] Z.Zong, F.Xie, S.Wang, et al., “Alanyl-tRNA Synthetase, AARS1, Is a Lactate Sensor and Lactyltransferase That Lactylates p53 and Contributes to Tumorigenesis,” Cell 187, no. 10 (2024):2375–2392.

[146] C.Raggi, M. L.Taddei, C.Rae, C.Braconi, and F.Marra, “Metabolic Reprogramming in Cholangiocarcinoma,” Journal of Hepatology 77, no. 3 (2022):849–864.

[147] Y.Yu, M.Liao, R.Liu, J. Chen, H.Feng, and Z.Fu, “Overexpression of Lactate Dehydrogenase-A in Human Intrahepatic Cholangiocarcinoma: Its Implication for Treatment,” World Journal of Surgical Oncology 12 (2014):78.

[148] Q.Zhou, Y.Yin, M.Yu, et al., “GTPBP4 Promotes Hepatocellular Carcinoma Progression and Metastasis via the PKM2 Dependent Glucose Metabolism,” Redox Biology 56 (2022):102458.

[149] K.McGrail, P.Granado-Martínez, R.Esteve-Puig, et al., “BRAF Activation by Metabolic Stress Promotes Glycolysis Sensitizing NRAS(Q61)-Mutated Melanomas to Targeted Therapy,” Nature Communications 13, no. 1 (2022):7113.

[150] L.Zhao, G.Ji, X.Le, et al., “Long Noncoding RNA LINC00092 Acts in Cancer-Associated Fibroblasts to Drive Glycolysis and Progression of Ovarian Cancer,” Cancer Research 77, no. 6 (2017):1369–1382.

[151] Q.Shi, Q.Shen, Y.Liu, et al., “Increased Glucose Metabolism in TAMs Fuels O-GlcNAcylation of Lysosomal Cathepsin B to Promote Cancer Metastasis and Chemoresistance,” Cancer Cell 40, no. 10 (2022):1207–1222 e10.

[152] P.Zhou, W.Chang, D.Gong, et al., “High Dietary Fructose Promotes Hepatocellular Carcinoma Progression by Enhancing O-GlcNAcylation via Microbiota-Derived Acetate,” Cell Metabolism 35, no. 11 (2023):1961–1975.

[153] C.Lehuédé, F.Dupuy, R.Rabinovitch, R. G.Jones, and P. M.Siegel, “Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis,” Cancer Research 76, no. 18 (2016):5201–5208.

[154] N. M.Iyengar, A.Gucalp, A. J.Dannenberg, and C. A.Hudis, “Obesity and Cancer Mechanisms: Tumor Microenvironment and Inflammation,” Journal of Clinical Oncology 34, no. 35 (2016):4270–4276.

[155] Q.Wu, B.Li, Z.Li, J.Li, S.Sun, and S. Sun, “Cancer-Associated Adipocytes: Key Players in Breast Cancer Progression,” Journal of Hematology &Oncology 12, no. 1 (2019):95.

[156] G. B.Ferraro, A.Ali, A.Luengo, et al., “Fatty Acid Synthesis Is Required for Breast Cancer Brain Metastasis,” Nature Cancer 2, no. 4 (2021):414–428.

[157] K. M.Nieman, H. A.Kenny, C. V.Penicka, et al., “Adipocytes Promote Ovarian Cancer Metastasis and Provide Energy for Rapid Tumor Growth,” Nature Medicine 17, no. 11 (2011):1498–1503.

[158] C.Zhang, Y.Liao, P.Liu, et al., “FABP5 Promotes Lymph Node Metastasis in Cervical Cancer by Reprogramming Fatty Acid Metabolism,” Theranostics 10, no. 15 (2020):6561–6580.

[159] F.Wu, J.Yang, J.Liu, et al., “Signaling Pathways in Cancer-Associated Fibroblasts and Targeted Therapy for Cancer,” Signal Transduction and Targeted Therapy 6, no. 1 (2021):218.

[160] M.Xiao, J.Xu, W.Wang, et al., “Functional Significance of Cholesterol Metabolism in Cancer: From Threat to Treatment,” Experimental &Molecular Medicine 55, no. 9 (2023):1982–1995.

[161] F. C. EVogel, A. BChaves-Filho, and A.Schulze, “Lipids as Mediators of Cancer Progression and Metastasis,” Nature Cancer 5, no. 1 (2024):16–29.

[162] C. ALyssiotis and A. C. Kimmelman, “Metabolic Interactions in the Tumor Microenvironment,” Trends in Cell Biology 27, no. 11 (2017):863–875.

[163] D.Mossmann, C.Müller, S.Park, et al., “Arginine Reprograms Metabolism in Liver Cancer via RBM39,” Cell 186, no. 23 (2023):5068–5083.

[164] L.Qian, N.Li, X. C.Lu, et al., “Enhanced BCAT1 Activity and BCAA Metabolism Promotes RhoC Activity in Cancer Progression,” Nature Metabolism 5, no. 7 (2023):1159–1173.

[165] Y.Ai, S.Luo, B.Wang, S. Xiao, and Y.Wang, “MiR-126-5p Promotes Tumor Cell Proliferation, Metastasis and Invasion by Targeting TDO2 in Hepatocellular Carcinoma,” Molecules 27, no. 2 (2022):443.

[166] H.Sun, H.Li, Y.Guan, et al., “BICC1 Drives Pancreatic Cancer Stemness and Chemoresistance by Facilitating Tryptophan Metabolism,” Science Advances 10, no. 25 (2024):eadj8650.

[167] M.Chen, Z. Y.Xiao, Z. P.Huang, et al., “Glycine Decarboxylase (GLDC) Plays a Crucial Role in Regulating Energy Metabolism, Invasion, Metastasis and Immune Escape for Prostate Cancer,” International Journal of Biological Sciences 19, no. 15 (2023):4726–4743.

[168] C.Liu, L.Wang, X.Liu, et al., “Cytoplasmic SHMT2 Drives the Progression and Metastasis of Colorectal Cancer by Inhibiting β-Catenin Degradation,” Theranostics 11, no. 6 (2021):2966–2986.

[169] J.Li, R.Kang, and D.Tang, “Cellular and Molecular Mechanisms of Perineural Invasion of Pancreatic Ductal Adenocarcinoma,” Cancer Communications 41, no. 8 (2021):642–660.

[170] Y.Zhang, H.Yu, J.Zhang, et al., “Cul4A-DDB1-Mediated Monoubiquitination of Phosphoglycerate Dehydrogenase Promotes Colorectal Cancer Metastasis via Increased S-Adenosylmethionine,” Journal of Clinical Investigation 131, no. 21 (2021):e146187.

[171] N. JMullen and P. K. Singh, “Nucleotide Metabolism: A Pan-Cancer Metabolic Dependency,” Nature Reviews Cancer 23, no. 5 (2023):275–294.

[172] D. D.Shi, M. R.Savani, K. G.Abdullah, and S. K.McBrayer, “Emerging Roles of Nucleotide Metabolism in Cancer,” Trends in Cancer 9, no. 8 (2023):624–635.

[173] C.Das, S.Adhikari, A.Bhattacharya, et al., “Epigenetic-Metabolic Interplay in the DNA Damage Response and Therapeutic Resistance of Breast Cancer,” Cancer Research 83, no. 5 (2023):657–666.

[174] A.Ohta, E.Gorelik, S. J.Prasad, et al., “A2A Adenosine Receptor Protects Tumors From Antitumor T Cells,” Proceedings of the National Academy of Sciences 103, no. 35 (2006):13132–13137.

[175] T.Scolaro, M.Manco, M.Pecqueux, et al., “Nucleotide Metabolism in Cancer Cells Fuels a UDP-Driven Macrophage Cross-Talk, Promoting Immunosuppression and Immunotherapy Resistance,” Nature Cancer 5, no. 8 (2024):1206–1226.

[176] X.Sun, W.Li, G.Li, et al., “A Novel Long Non-Coding RNA LINC00524 Facilitates Invasion and Metastasis Through Interaction With TDP43 in Breast Cancer,” Journa of Cellular and Molecular Medicine 28, no. 8 (2024):e18275.

[177] C. C.Kuo, J. Y.Wu, and K. K.Wu, “Cancer-Derived Extracellular Succinate: A Driver of Cancer Metastasis,” Journal of Biomedical Science 29, no. 1 (2022):93.

[178] G.Sun, S.Zhao, Z.Fan, et al., “CHSY1 Promotes CD8(+) T Cell Exhaustion Through Activation of Succinate Metabolism Pathway Leading to Colorectal Cancer Liver Metastasis Based on CRISPR/Cas9 Screening,” Journal of Experimental &Clinical Cancer Research 42, no. 1 (2023):248.

[179] H.Colvin, N.Nishida, M.Konno, et al., “Oncometabolite D-2-Hydroxyglurate Directly Induces Epithelial–Mesenchymal Transition and Is Associated With Distant Metastasis in Colorectal Cancer,” Scientific Reports 6 (2016):36289.

[180] K.Xiang, M.Kunin, S.Larafa, et al., “α-Ketoglutarate Supplementation and NAD+Modulation Enhance Metabolic Rewiring and Radiosensitization in SLC25A1 Inhibited Cancer Cells,” Cell Death Discovery 10, no. 1 (2024):27.

[181] Z.Zhou and Z. R. Lu, “Molecular Imaging of the Tumor Microenvironment,” Advanced Drug Delivery Reviews 113 (2017):24–48.

[182] D.Hanahan and R. A. Weinberg, “Hallmarks of Cancer: The Next Generation,” Cell 144, no. 5 (2011):646–674.

[183] K. C.Corn, M. A.Windham, and M.Rafat, “Lipids in the Tumor Microenvironment: From Cancer Progression to Treatment,” Progress in Lipid Research 80 (2020):101055.

[184] T.Wu and Y.Dai, “Tumor Microenvironment and Therapeutic Response,” Cancer Letters 387 (2017):61–68.

[185] X.Jing, F.Yang, C.Shao, et al., “Role of Hypoxia in Cancer Therapy by Regulating the Tumor Microenvironment,” Molecular Cancer 18, no. 1 (2019):157.

[186] O.Elhanani, R.Ben-Uri, and L.Keren, “Spatial Profiling Technologies Illuminate the Tumor Microenvironment,” Cancer Cell 41, no. 3 (2023):404–420.

[187] Y.Chen, D.Wang, Y.Li, et al., “Spatiotemporal Single-Cell Analysis Decodes Cellular Dynamics Underlying Different Responses to Immunotherapy in Colorectal Cancer,” Cancer Cell 42, no. 7 (2024):1268–1285.

[188] S.Schwörer, F. V. Cimino, M.Ros, et al., “Hypoxia Potentiates the Inflammatory Fibroblast Phenotype Promoted by Pancreatic Cancer Cell-Derived Cytokines,” Cancer Research 83, no. 10 (2023):1596–1610.

[189] V.Petrova, M.Annicchiarico-Petruzzelli, G.Melino, and I.Amelio, “The Hypoxic Tumour Microenvironment,” Oncogenesis 7, no. 1 (2018):10.

[190] E.Boedtkjer and S. F. Pedersen, “The Acidic Tumor Microenvironment as a Driver of Cancer,” Annual Review of Physiology 82 (2020):103–126.

[191] B.Ritter and F. R. Greten, “Modulating Inflammation for Cancer Therapy,” Journal of Experimental Medicine 216, no. 6 (2019):1234–1243.

[192] K. S. NAtretkhany, M. S. Drutskaya, S. A.Nedospasov, S. I.Grivennikov, and D. V. Kuprash, “Chemokines, Cytokines and Exosomes Help Tumors to Shape Inflammatory Microenvironment,” Pharmacology &Therapeutics 168 (2016):98–112.

[193] K. E.de Visser and J. A. Joyce, “The Evolving Tumor Microenvironment: From Cancer Initiation to Metastatic Outgrowth,” Cancer Cell 41, no. 3 (2023):374–403.

[194] X.Wang, R.Lopez, R. A.Luchtel, S.Hafizi, B.Gartrell, and N.Shenoy, “Immune Evasion in Renal Cell Carcinoma: Biology, Clinical Translation, Future Directions,” Kidney International 99, no. 1 (2021):75–85.

[195] B.He, R.Gao, S.Lv, et al., “Cancer Cell Employs a Microenvironmental Neural Signal Trans-Activating Nucleus-Mitochondria Coordination to Acquire Stemness,” Signal Transduction and Targeted Therapy 8, no. 1 (2023):275.

[196] P.Nallasamy, R. K.Nimmakayala, S.Parte, A. C.Are, S. K.Batra, and M. P.Ponnusamy, “Tumor Microenvironment Enriches the Stemness Features: The Architectural Event of Therapy Resistance and Metastasis,” Molecular Cancer 21, no. 1 (2022):225.

[197] P.Verma, N.Shukla, S.Kumari, M. S.Ansari, N. K.Gautam, and G. K.Patel, “Cancer Stem Cell in Prostate Cancer Progression, Metastasis and Therapy Resistance,” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1878, no. 3 (2023):188887.

[198] P. E.Saw, Q.Liu, P. P.Wong, and E. Song, “Cancer Stem Cell Mimicry for Immune Evasion and Therapeutic Resistance,” Cell Stem Cell 31, no. 8 (2024):1101–1112.

[199] Y.Wang, R.Narasimamurthy, M.Qu, et al., “Circadian Regulation of Cancer Stem Cells and the Tumor Microenvironment During Metastasis,” Nature Cancer 5, no. 4 (2024):546–556.

[200] Y.Chen, K. M.McAndrews, and R.Kalluri, “Clinical and Therapeutic Relevance of Cancer-Associated Fibroblasts,” Nature Reviews Clinical Oncology 18, no. 12 (2021):792–804.

[201] T. X.Huang, X. Y.Tan, H. S.Huang, et al., “Targeting Cancer-Associated Fibroblast-Secreted WNT2 Restores Dendritic Cell-Mediated Antitumour Immunity,” Gut 71, no. 2 (2022):333–344.

[202] Y.Chhabra and A. T. Weeraratna, “Fibroblasts in Cancer: Unity in Heterogeneity,” Cell 186, no. 8 (2023):1580–1609.

[203] H.Choi and A.Moon, “Crosstalk Between Cancer Cells and Endothelial Cells: Implications for Tumor Progression and Intervention,” Archives of Pharmacal Research 41, no. 7 (2018):711–724.

[204] J.Liu, X.Yu, A.Braucht, S. Smith, and C.Wang, “N-Cadherin Targeted Melanin Nanoparticles Reverse the Endothelial-Mesenchymal Transition in Vascular Endothelial Cells to Potentially Slow the Progression of Atherosclerosis and Cancer,” ACS Nano 18, no. 11 (2024):8229–8247.

[205] Q. Q.Li, M.Guo, G. H.He, et al., “VEGF-Induced Nrdp1 Deficiency in Vascular Endothelial Cells Promotes Cancer Metastasis by Degrading Vascular Basement Membrane,” Oncogene 43, no. 24 (2024):1836–1851.

[206] C. C.Picoli, B. Ô. P. Gonçalves, G. S. P. Santos, et al., “Pericytes Cross-Talks Within the Tumor Microenvironment,” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1876, no. 2 (2021):188608.

[207] Y.Wang, Q.Sun, Y.Ye, et al., “FGF-2 Signaling in Nasopharyngeal Carcinoma Modulates Pericyte-Macrophage Crosstalk and Metastasis,” JCI Insight 7, no. 10 (2022):157874.

[208] X.Li, J.Pan, T.Liu, et al., “Novel TCF21(high) Pericyte Subpopulation Promotes Colorectal Cancer Metastasis by Remodelling Perivascular Matrix,” Gut 72, no. 4 (2023):710–721.

[209] F. R.Balkwill, M.Capasso, and T.Hagemann, “The Tumor Microenvironment at a Glance,” Journal of Cell Science 125, no. Pt 23 (2012):5591–5596.

[210] N. MAnderson and M. C. Simon, “The Tumor Microenvironment,” Current Biology 30, no. 16 (2020):R921–R925.

[211] B.Toledo, L.Zhu Chen, M.Paniagua-Sancho, J. A.Marchal, M.Perán, and E.Giovannetti, “Deciphering the Performance of Macrophages in Tumour Microenvironment: A Call for Precision Immunotherapy,” Journal of Hematology &Oncology 17, no. 1 (2024):44.

[212] A.Mantovani, P.Allavena, F.Marchesi, and C.Garlanda, “Macrophages as Tools and Targets in Cancer Therapy,” Nature Reviews Drug Discovery 21, no. 11 (2022):799–820.

[213] L.Cassetta and J. W. Pollard, “A Timeline of Tumour-Associated Macrophage Biology,” Nature Reviews Cancer 23, no. 4 (2023):238–257.

[214] R. Y.Ma, H.Zhang, X. F.Li, et al., “Monocyte-Derived Macrophages Promote Breast Cancer Bone Metastasis Outgrowth,” Journal of Experimental Medicine 217, no. 11 (2020):e20191820.

[215] P.Bieniasz-Krzywiec, R. Martín-Pérez, M.Ehling, et al., “Podoplanin-Expressing Macrophages Promote Lymphangiogenesis and Lymphoinvasion in Breast Cancer,” Cell Metabolism 30, no. 5 (2019):917–936.

[216] S. R.Ali, M.Jordan, P.Nagarajan, and M.Amit, “Nerve Density and Neuronal Biomarkers in Cancer,” Cancers 14, no. 19 (2022):4817.

[217] L.Hui and Y.Chen, “Tumor Microenvironment: Sanctuary of the Devil,” Cancer Letters 368, no. 1 (2015):7–13.

[218] A.El-Kenawi, K.Hänggi, and B.Ruffell, “The Immune Microenvironment and Cancer Metastasis,” Cold Spring Harbor Perspectives in Medicine 10, no. 4 (2020):a037424.

[219] S.Jaillon, A.Ponzetta, D.Di Mitri, A.Santoni, R.Bonecchi, and A.Mantovani, “Neutrophil Diversity and Plasticity in Tumour Progression and Therapy,” Nature Reviews Cancer 20, no. 9 (2020):485–503.

[220] L.Yang, Y. T.He, S.Dong, et al., “Single-Cell Transcriptome Analysis Revealed a Suppressive Tumor Immune Microenvironment in EGFR Mutant Lung Adenocarcinoma,” Journal for Immunotherapy of Cancer 10, no. 2 (2022):e003534.

[221] M. P.Plebanek, Y.Xue, Y. V.Nguyen, et al., “A Lactate-SREBP2 Signaling Axis Drives Tolerogenic Dendritic Cell Maturation and Promotes Cancer Progression,” Science Immunology 9, no. 95 (2024):eadi4191.

[222] M.Friedrich, M.Hahn, J.Michel, et al., “Dysfunctional Dendritic Cells Limit Antigen-Specific T Cell Response in Glioma,” Neuro-Oncology 25, no. 2 (2023):263–276.

[223] S. MDowns-Canner, J. Meier, B. G.Vincent, and J. S.Serody, “B Cell Function in the Tumor Microenvironment,” Annual Review of Immunology 40 (2022):169–193.

[224] D. GDeNardo and B.Ruffell, “Macrophages as Regulators of Tumour Immunity and Immunotherapy,” Nature Reviews Immunology 19, no. 6 (2019):369–382.

[225] A.Mantovani and P.Allavena, “The Interaction of Anticancer Therapies With Tumor-Associated Macrophages,” Journal of Experimental Medicine 212, no. 4 (2015):435–445.

[226] C. JLogothetis and S. H. Lin, “Osteoblasts in Prostate Cancer Metastasis to Bone,” Nature Reviews Cancer 5, no. 1 (2005):21–28.

[227] J.Kang, F.La Manna, F.Bonollo, et al., “Tumor Microenvironment Mechanisms and Bone Metastatic Disease Progression of Prostate Cancer,” Cancer Letters 530 (2022):156–169.

[228] C.Zuo, J.Xia, and L.Chen, “Dissecting Tumor Microenvironment From Spatially Resolved Transcriptomics Data by Heterogeneous Graph Learning,” Nature Communications 15, no. 1 (2024):5057.

[229] Y.Wang, J.Jia, F.Wang, et al., “Pre-Metastatic Niche: Formation, Characteristics and Therapeutic Implication,” Signal Transduction and Targeted Therapy 9, no. 1 (2024):236.

[230] S.Hirakawa, S.Kodama, R.Kunstfeld, K.Kajiya, L. F.Brown, and M.Detmar, “VEGF-A Induces Tumor and Sentinel Lymph Node Lymphangiogenesis and Promotes Lymphatic Metastasis,” The Journal of Experimental Medicine 201, no. 7 (2005):1089–1099.

[231] Z.Gong, Q.Li, J.Shi, et al., “Lung Fibroblasts Facilitate Pre-Metastatic Niche Formation by Remodeling the Local Immune Microenvironment,” Immunity 55, no. 8 (2022):1483–1500.

[232] Z.Wang, S. Y.Kim, W.Tu, et al., “Extracellular Vesicles in Fatty Liver Promote a Metastatic Tumor Microenvironment,” Cell Metabolism 35, no. 7 (2023):1209–1226.e13.

[233] F. JLowery and D.Yu, “Brain Metastasis: Unique Challenges and Open Opportunities,” Biochimica et Biophysica Acta (BBA)—Reviews on Cancer 1867, no. 1 (2017):49–57.

[234] J.Arnold, J.Schattschneider, C.Blechner, et al., “Tubulin Tyrosine Ligase Like 4 (TTLL4) Overexpression in Breast Cancer Cells Is Associated With Brain Metastasis and Alters Exosome Biogenesis,” Journal of Experimental &Clinical Cancer Research 39, no. 1 (2020):205.

[235] Z.Yue, X.Niu, Z.Yuan, et al., “RSPO2 and RANKL Signal Through LGR4 to Regulate Osteoclastic Premetastatic Niche Formation and Bone Metastasis,” Journal of Clinical Investigation 132, no. 2 (2022):e144579.

[236] Q.Zhang, R.Abdo, C.Iosef, et al., “The Spatial Transcriptomic Landscape of Non-Small Cell Lung Cancer Brain Metastasis,” Nature Communications 13, no. 1 (2022):5983.

[237] C.Corti, G.Antonarelli, C.Criscitiello, et al., “Targeting Brain Metastases in Breast Cancer,” Cancer Treatment Reviews 103 (2022):102324.

[238] X.Zhang, “Interactions Between Cancer Cells and Bone Microenvironment Promote Bone Metastasis in Prostate Cancer,” Cancer Communications 39, no. 1 (2019):76.

[239] C.Wang, A.Nagayach, H.Patel, et al., “Utilizing Human Cerebral Organoids to Model Breast Cancer Brain Metastasis in Culture,” Breast Cancer Research 26, no. 1 (2024):108.

[240] R. B.Berish, A. N.Ali, P. G.Telmer, J. A. Ronald, and H. S.Leong, “Translational Models of Prostate Cancer Bone Metastasis,” Nature Reviews Urology 15, no. 7 (2018):403–421.

[241] G. B.Frisoni, M.Boccardi, F.Barkhof, et al., “Strategic Roadmap for an Early Diagnosis of Alzheimer’s Disease Based on Biomarkers,” Lancet Neurology 16, no. 8 (2017):661–676.

[242] R.Kandimalla, J.Xu, A.Link, et al., “EpiPanGI Dx: A Cell-Free DNA Methylation Fingerprint for the Early Detection of Gastrointestinal Cancers,” Clinical Cancer Research 27, no. 22 (2021):6135–6144.

[243] C. G.Huang, Q.Liu, S. T.Zheng, et al., “Chemokines and Their Receptors: Predictors of Therapeutic Potential in Tumor Microenvironment on Esophageal Cancer,” Digestive Diseases and Sciences 69, no. 5 (2024):1562–1570.

[244] F.Meric-Bernstam, J. Larkin, J.Tabernero, and C.Bonini, “Enhancing Anti-Tumour Efficacy With Immunotherapy Combinations,” Lancet 397, no. 10278 (2021):1010–1022.

[245] L. BKennedy and A. K. S. Salama, “A Review of Cancer Immunotherapy Toxicity,” CA: A Cancer Journal for Clinicians 70, no. 2 (2020):86–104.

[246] A.Rezvan, G.Romain, M.Fathi, et al., “Identification of a Clinically Efficacious CAR T Cell Subset in Diffuse Large B Cell Lymphoma by Dynamic Multidimensional Single-Cell Profiling,” Nature Cancer 5, no. 7 (2024):1010–1023.

[247] L.Wei, J.Wang, E.Lampert, et al., “Intratumoral and Intertumoral Genomic Heterogeneity of Multifocal Localized Prostate Cancer Impacts Molecular Classifications and Genomic Prognosticators,” European Urology 71, no. 2 (2017):183–192.

[248] S. E.Eggener, R. B.Rumble, A. J.Armstrong, et al., “Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline,” Journal of Clinical Oncology 38, no. 13 (2020):1474–1494.

[249] D.Kwapisz, “The First Liquid Biopsy Test Approved. Is It a New Era of Mutation Testing for Non-Small Cell Lung Cancer?,” Annals of Translational Medicine 5, no. 3 (2017):46.

[250] M.Marcuello, V.Vymetalkova, R. P. L.Neves, et al., “Circulating Biomarkers for Early Detection and Clinical Management of Colorectal Cancer,” Molecular Aspects of Medicine 69 (2019):107–122.

[251] Y.Zhang, T.Han, D.Feng, et al., “Screening of Non-Invasive miRNA Biomarker Candidates for Metastasis of Gastric Cancer by Small RNA Sequencing of Plasma Exosomes,” Carcinogenesis 41, no. 5 (2020):582–590.

[252] B. Y.Nabet, M. S.Esfahani, E. J.Moding, et al., “Noninvasive Early Identification of Therapeutic Benefit From Immune Checkpoint Inhibition,” Cell 183, no. 2 (2020):363–376.e13.

[253] C.Abbosh, A. M.Frankell, T.Harrison, et al., “Tracking Early Lung Cancer Metastatic Dissemination in TRACERx Using CtDNA,” Nature 616, no. 7957 (2023):553–562.

[254] J.Cai, C.Zeng, W.Hua, et al., “An Integrative Analysis of Genome-Wide 5-Hydroxymethylcytosines in Circulating Cell-Free DNA Detects Noninvasive Diagnostic Markers for Gliomas,” Neuro-Oncology Advances 3, no. 1 (2021):vdab049.

[255] B.Wang, Y.Zhao, Y.Li, et al., “A Plasma SNORD33 Signature Predicts Platinum Benefit in Metastatic Triple-Negative Breast Cancer Patients,” Molecular Cancer 21, no. 1 (2022):22.

[256] D.Croci, R.Santalla Méndez, S.Temme, et al., “Multispectral Fluorine-19 MRI Enables Longitudinal and Noninvasive Monitoring of Tumor-Associated Macrophages,” Science Translational Medicine 14, no. 667 (2022):eabo2952.

[257] E.Kartal, T. S. B. Schmidt, E.Molina-Montes, et al., “A Faecal Microbiota Signature With High Specificity for Pancreatic Cancer,” Gut 71, no. 7 (2022):1359–1372.

[258] K. M.Kanninen, N.Bister, J.Koistinaho, and T.Malm, “Exosomes As New Diagnostic Tools in CNS Diseases,” Biochimica et Biophysica Acta (BBA)—Molecular Basis of Disease 1862, no. 3 (2016):403–410.

[259] M.Poggio, T.Hu, C. C.Pai, et al., “Suppression of Exosomal PD-L1 Induces Systemic Anti-Tumor Immunity and Memory,” Cell 177, no. 2 (2019):414–427.

[260] G.Rodrigues, A.Hoshino, C. M.Kenific, et al., “Tumour Exosomal CEMIP Protein Promotes Cancer Cell Colonization in Brain Metastasis,” Nature Cell Biology 21, no. 11 (2019):1403–1412.

[261] S.Chen, Y.Xu, W.Zhuo, and L. Zhang, “The Emerging Role of Lactate in Tumor Microenvironment and Its Clinical Relevance,” Cancer Letters 590 (2024):216837.

[262] Z.Zhao, J.Qin, Y.Qian, et al., “FFAR2 Expressing Myeloid-Derived Suppressor Cells Drive Cancer Immunoevasion,” Journal of Hematology &Oncology 17, no. 1 (2024):9.

[263] L.Ricci, F. U.Stanley, T.Eberhart, F.Mainini, D.Sumpton, and S.Cardaci, “Pyruvate Transamination and NAD Biosynthesis Enable Proliferation of Succinate Dehydrogenase-Deficient Cells by Supporting Aerobic Glycolysis,” Cell Death &Disease 14, no. 7 (2023):403.

[264] D.Hanahan, “Hallmarks of Cancer: New Dimensions,” Cancer Discovery 12, no. 1 (2022):31–46.

[265] M.Békés, D. R. Langley, and C. M.Crews, “PROTAC Targeted Protein Degraders: The Past Is Prologue,” Nature Reviews Drug Discovery 21, no. 3 (2022):181–200.

[266] P. L.Bedard, D. M.Hyman, M. S.Davids, and L. L. Siu, “Small Molecules, Big Impact:20 years of Targeted Therapy in Oncology,” Lancet 395, no. 10229 (2020):1078–1088.

[267] S.Morgan, P.Grootendorst, J.Lexchin, C.Cunningham, and D.Greyson, “The Cost of Drug Development: A Systematic Review,” Health Policy 100, no. 1 (2011):4–17.

[268] S.Prasad, S. C.Gupta, and B. B.Aggarwal, “Serendipity in Cancer Drug Discovery: Rational or Coincidence?,” Trends in Pharmacological Sciences 37, no. 6 (2016):435–450.

[269] S.Chen, Y.Zhao, S.Liu, et al., “Epigenetic Enzyme Mutations as Mediators of Anti-Cancer Drug Resistance,” Drug Resistance Updates 61 (2022):100821.

[270] N.Harbeck and M.Gnant, “Breast Cancer,” Lancet 389, no. 10074 (2017):1134–1150.

[271] G. R.Khosravi, S.Mostafavi, S.Bastan, N.Ebrahimi, R. S.Gharibvand, and N.Eskandari, “Immunologic Tumor Microenvironment Modulators for Turning Cold Tumors Hot,” Cancer Communications 44, no. 5 (2024):521–553.

[272] R.Roskoski, Jr., “Properties of FDA-Approved Small Molecule Protein Kinase Inhibitors: A 2024 Update,” Pharmacological Research 200 (2024):107059.

[273] Y.Wang, J.Wu, H.Chen, et al., “Genome-Wide CRISPR-Cas9 Screen Identified KLF11 as a Druggable Suppressor for Sarcoma Cancer Stem Cells,” Science Advances 7, no. 5 (2021):eabe3445.

[274] I.Baccelli, Y.Gareau, B.Lehnertz, et al., “Mubritinib Targets the Electron Transport Chain Complex I and Reveals the Landscape of OXPHOS Dependency in Acute Myeloid Leukemia,” Cancer Cell 36, no. 1 (2019):84–99.

[275] Y.Shi, X.Wang, Y.Meng, et al., “A Novel Mechanism of Endoplasmic Reticulum Stress-and c-Myc-Degradation-Mediated Therapeutic Benefits of Antineurokinin-1 Receptor Drugs in Colorectal Cancer,” Advanced Science 8, no. 21 (2021):e2101936.

[276] N.Gupta and S. K. Srivastava, “Atovaquone: An Antiprotozoal Drug Suppresses Primary and Resistant Breast Tumor Growth by Inhibiting HER2/β-Catenin Signaling,” Molecular Cancer Therapeutics 18, no. 10 (2019):1708–1720.

[277] I.Kaushik, S.Ramachandran, S.Prasad, and S. K.Srivastava, “Drug Rechanneling: A Novel Paradigm for Cancer Treatment,” Seminars in Cancer Biology 68 (2021):279–290.

[278] M.Baretti, L.Danilova, J. N.Durham, et al., “Entinostat in Combination With Nivolumab in Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Clinical Trial,” Nature Communications 15, no. 1 (2024):9801.

[279] Q. S. CChu, T. O.Nielsen, T.Alcindor, et al., “A Phase Ii Study of SB939, a Novel Pan-Histone Deacetylase Inhibitor, in Patients With Translocation-Associated Recurrent/Metastatic Sarcomas—NCIC-CTG IND 200,” Annals of Oncology 26, no. 5 (2015):973–981.

[280] T. Z.Zeleke, Q.Pan, C.Chiuzan, et al., “Network-Based Assessment of HDAC6 Activity Predicts Preclinical and Clinical Responses to the HDAC6 Inhibitor Ricolinostat in Breast Cancer,” Nature Cancer 4, no. 2 (2023):257–275.

[281] X.Yang, H.Han, D. D.De Carvalho, F. D.Lay, P. A.Jones, and G.Liang, “Gene Body Methylation Can Alter Gene Expression and Is a Therapeutic Target in Cancer,” Cancer Cell 26, no. 4 (2014):577–590.

[282] J.Bhadury, L. M.Nilsson, S.Veppil Muralidharan, et al., “BET and HDAC Inhibitors Induce Similar Genes and Biological Effects and Synergize to Kill in Myc-Induced Murine Lymphoma,” Proceedings of the National Academy of Sciences 111, no. 26 (2014): E2721–E2730.

[283] A. E.Kam, A.Masood, and R. T.Shroff, “Current and Emerging Therapies for Advanced Biliary Tract Cancers,” Lancet Gastroenterology &Hepatology 6, no. 11 (2021):956–969.

[284] S. Y.Kim, X.Zhang, G. G.Schiattarella, et al., “Epigenetic Reader BRD4 (Bromodomain-Containing Protein 4) Governs Nucleus-Encoded Mitochondrial Transcriptome to Regulate Cardiac Function,” Circulation 142, no. 24 (2020):2356–2370.

[285] C.Berthon, E.Raffoux, X.Thomas, et al., “Bromodomain Inhibitor OTX015 in Patients With Acute Leukaemia: A Dose-Escalation, Phase 1 Study,” Lancet Haematology 3, no. 4 (2016): e186–e195.

[286] G. I.Shapiro, P.LoRusso, A.Dowlati, et al., “A Phase 1 Study of RO6870810, a Novel Bromodomain and Extra-Terminal Protein Inhibitor, in Patients With Nut Carcinoma, Other Solid Tumours, or Diffuse Large B-Cell Lymphoma,” British Journal of Cancer 124, no. 4 (2021):744–753.

[287] A. M.Vargason, A. C.Anselmo, and S.Mitragotri, “The Evolution of Commercial Drug Delivery Technologies,” Nature Biomedical Engineering 5, no. 9 (2021):951–967.

[288] N.Hosen, Y.Matsunaga, K.Hasegawa, et al., “The Activated Conformation of Integrin β7 Is a Novel Multiple Myeloma–Specific Target for CAR T Cell Therapy,” Nature Medicine 23, no. 12 (2017):1436–1443.

[289] B. S.Pan, S. A.Perera, J. A.Piesvaux, et al., “An Orally Available Non-Nucleotide STING Agonist With Antitumor Activity,” Science 369, no. 6506 (2020):eaba6098.

[290] C.Pan, O.Schoppe, A.Parra-Damas, et al., “Deep Learning Reveals Cancer Metastasis and Therapeutic Antibody Targeting in the Entire Body,” Cell 179, no. 7 (2019):1661–1676.e19.

[291] A.Thomas, B. A.Teicher, and R.Hassan, “Antibody-Drug Conjugates for Cancer Therapy,” Lancet Oncology 17, no. 6 (2016): e254–e262.

[292] A. M.Scott, J. D.Wolchok, and L. J.Old, “Antibody Therapy of Cancer,” Nature Reviews Cancer 12, no. 4 (2012):278–287.

[293] I.Abánades Lázaro, M.Vicent-Morales, G. Mínguez Espallargas, and M.Giménez-Marqués, “Hierarchical Mesoporous NanoMUV-2 for the Selective Delivery of Macromolecular Drugs,” Journal of Materials Chemistry B 11, no. 38 (2023):9179–9184.

[294] H.Chen, T.Yu, L.Lin, et al., “γ-Secretase Inhibitors Augment Efficacy of BCMA-Targeting Bispecific Antibodies Against Multiple Myeloma Cells Without Impairing T-Cell Activation and Differentiation,” Blood Cancer Journal 12, no. 8 (2022):118.

[295] S.Bagchi, R.Yuan, and E. G.Engleman, “Immune Checkpoint Inhibitors for the Treatment of Cancer: Clinical Impact and Mechanisms of Response and Resistance,” Annual Review of Pathology: Mechanisms of Disease 16 (2021):223–249.

[296] C.Wang, Q.Zeng, Z. M.Gül, et al., “Circadian Tumor Infiltration and Function of CD8(+) T Cells Dictate Immunotherapy Efficacy,” Cell 187, no. 11 (2024):2690–2702.

[297] C. H.June, R. S.O’Connor, O. U.Kawalekar, S.Ghassemi, and M. C. Milone, “CAR T Cell Immunotherapy for Human Cancer,” Science 359, no. 6382 (2018):1361–1365.

[298] S. J.Schuster, M. R.Bishop, C. S.Tam, et al., “Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma,” New England Journal of Medicine 380, no. 1 (2019):45–56.

[299] F. L.Locke, D. B.Miklos, C. A.Jacobson, et al., “Axicabtagene Ciloleucel as Second-Line Therapy for Large B-Cell Lymphoma,” New England Journal of Medicine 386, no. 7 (2022):640–654.

[300] R. CSterner and R. M. Sterner, “Car-T Cell Therapy: Current Limitations and Potential Strategies,” Blood Cancer Journal 11, no. 4 (2021):69.

[301] M. ACheever and C. S. Higano, “PROVENGE (Sipuleucel-T) in Prostate Cancer: The First FDA-Approved Therapeutic Cancer Vaccine,” Clinical Cancer Research 17, no. 11 (2011):3520–3526.

[302] L. MSly and D. M. McKay, “Macrophage Immunotherapy: Overcoming Impediments to Realize Promise,” Trends in Immunology 43, no. 12 (2022):959–968.

[303] A.Valeri, A.García-Ortiz, E.Castellano, et al., “Overcoming Tumor Resistance Mechanisms in CAR-NK Cell Therapy,” Frontiers in Immunology 13 (2022):953849.

[304] G.Xie, H.Dong, Y.Liang, J. D. Ham, R.Rizwan, and J.Chen, “CAR-NK Cells: A Promising Cellular Immunotherapy for Cancer,” EBioMedicine 59 (2020):102975.

[305] E.Liu, D.Marin, P.Banerjee, et al., “Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors,” New England Journal of Medicine 382, no. 6 (2020):545–553.

[306] Y.Chang, X.Cai, R.Syahirah, et al., “CAR-Neutrophil Mediated Delivery of Tumor-Microenvironment Responsive Nanodrugs for Glioblastoma Chemo-Immunotherapy,” Nature Communications 14, no. 1 (2023):2266.

[307] V.Poli and I.Zanoni, “Neutrophil Intrinsic and Extrinsic Regulation of NETosis in Health and Disease,” Trends in Microbiology 31, no. 3 (2023):280–293.

[308] P.Ferrari, C.Scatena, M.Ghilli, I.Bargagna, G.Lorenzini, and A.Nicolini, “Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC,” International Journal of Molecular Sciences 23, no. 3 (2022):1665.

[309] Y.Pan, J.Cheng, Y.Zhu, J. Zhang, W.Fan, and X.Chen, “Immunological Nanomaterials to Combat Cancer Metastasis,” Chemical Society Reviews 53, no. 12 (2024):6399–6444.

[310] K.Zhang, C.Qi, and K.Cai, “Manganese-Based Tumor Immunotherapy,” Advanced Materials 35, no. 19 (2023):e2205409.

[311] Z.Wang, D.Hao, Y.Wang, et al., “Peptidyl Virus-Like Nanovesicles as Reconfigurable “Trojan Horse”for Targeted siRNA Delivery and Synergistic Inhibition of Cancer Cells,” Small 19, no. 1 (2023):e2204959.

[312] D.Lorusso, Y.Xiang, K.Hasegawa, et al., “Pembrolizumab or Placebo Wit Chemoradiotherapy Followed by Pembrolizumab or Placebo for Newly Diagnosed, High-Risk, Locally Advanced Cervical Cancer (ENGOT-cx11/GOG-3047/KEYNOTE-A18): A Randomised, Double-Blind, Phase 3 Clinical Trial,” Lancet 403, no. 10434 (2024):1341–1350.

[313] Z. A.Wainberg, D.Melisi, T.Macarulla, et al., “NALIRIFOX Versus Nab-Paclitaxel and Gemcitabine in Treatment-Naive Patients With Metastatic Pancreatic Ductal Adenocarcinoma (NAPOLI 3): A Randomised, Open-Label, Phase 3 Trial,” Lancet 402, no. 10409 (2023):1272–1281.

[314] Y.Agarwala, T. A.Brauns, A. E.Sluder, M. C.Poznansky, and Y.Gemechu, “Targeting Metabolic Pathways to Counter Cancer Immunotherapy Resistance,” Trends in Immunology 45, no. 7 (2024):486–494.

[315] Y.Wu, J.Ma, X.Yang, et al., “Neutrophil Profiling Illuminates Anti-Tumor Antigen-Presenting Potency,” Cell 187, no. 6 (2024):1422–1439.

[316] Y.Rong, Y.Ning, J.Zhu, et al., “Oncolytic Adenovirus Encoding Decorin and CD40 Ligand Inhibits Tumor Growth and Liver Metastasis via Immune Activation in Murine Colorectal Tumor Model,” Molecular Biomedicine 5, no. 1 (2024):39.

[317] X.Yang, Y.Wang, R.Byrne, G. Schneider, and S.Yang, “Concepts of Artificial Intelligence for Computer-Assisted Drug Discovery,” Chemical Reviews 119, no. 18 (2019):10520–10594.

[318] P. AKulkarni and H.Singh, “Artificial Intelligence in Clinical Diagnosis: Opportunities, Challenges, and Hype,” Journal of the American Medical Association 330, no. 4 (2023):317–318.

[319] R.Han, J. N.Acosta, Z.Shakeri, J. P. A.Ioannidis, E. J. Topol, and P.Rajpurkar, “Randomised Controlled Trials Evaluating Artificial Intelligence in Clinical Practice: A Scoping Review,” Lancet Digital Health 6, no. 5 (2024): e367–e373.

[320] S. A.Dugger, A.Platt, and D. B.Goldstein, “Drug Development in the Era of Precision Medicine,” Nature Reviews Drug Discovery 17, no. 3 (2018):183–196.

[321] F.Zhong, X.Wu, R.Yang, et al., “Drug Target Inference by Mining Transcriptional Data Using a Novel Graph Convolutional Network Framework,” Protein &Cell 13, no. 4 (2022):281–301.

[322] R. TDadu and C. M. Ballantyne, “Lipid Lowering With PCSK9 Inhibitors,” Nature Reviews Cardiology 11, no. 10 (2014):563–575.

[323] W. H.Abuwatfa, W. G.Pitt, and G. A.Husseini, “Scaffold-Based 3D Cell Culture Models in Cancer Research,” Journal of Biomedical Science 31, no. 1 (2024):7.

[324] Y.Liu, W.Wu, C.Cai, H. Zhang, H.Shen, and Y.Han, “Patient-Derived Xenograft Models in Cancer Therapy: Technologies and Applications,” Signal Transduction and Targeted Therapy 8, no. 1 (2023):160.

[325] J.Chuprin, H.Buettner, M. O.Seedhom, et al., “Humanized Mouse Models for Immuno-Oncology Research,” Nature Reviews Clinical Oncology 20, no. 3 (2023):192–206.

[326] T. T.Truong, S.Mondal, V. H. M.Doan, et al., “Precision-Engineered Metal and Metal-Oxide Nanoparticles for Biomedical Imaging and Healthcare Applications,” Advances in Colloid and Interface Science 332 (2024):103263.

[327] A.Marusyk, M.Janiszewska, and K.Polyak, “Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance,” Cancer Cell 37, no. 4 (2020):471–484.

[328] Y.Li, E.Porta-Pardo, C.Tokheim, et al., “Pan-Cancer Proteogenomics Connects Oncogenic Drivers to Functional States,” Cell 186, no. 18 (2023):3921–3944.

[329] Q.Zhan, C.Wen, Y.Zhao, et al., “Identification of Copy Number Variation-Driven Molecular Subtypes Informative for Prognosis and Treatment in Pancreatic Adenocarcinoma of a Chinese Cohort,” EBioMedicine 74 (2021):103716.

[330] Z.Hu, M.Artibani, A.Alsaadi, et al., “The Repertoire of Serous Ovarian Cancer Non-Genetic Heterogeneity Revealed by Single-Cell Sequencing of Normal Fallopian Tube Epithelial Cells,” Cancer Cell 37, no. 2 (2020):226–242.e7.

[331] F.Bertolini, V. P.Sukhatme, and G.Bouche, “Drug Repurposing in Oncology–Patient and Health Systems Opportunities,” Nature Reviews Clinical Oncology 12, no. 12 (2015):732–742.

[332] Z.Feng, Y.Xia, T.Gao, et al., “The Antipsychotic Agent Trifluoperazine Hydrochloride Suppresses Triple-Negative Breast Cancer Tumor Growth and Brain Metastasis by Inducing G0/G1 Arrest and Apoptosis,” Cell Death &Disease 9, no. 10 (2018):1006.

[333] D. GRyan and L. A. J. O’Neill, “Krebs Cycle Reborn in Macrophage Immunometabolism,” Annual Review of Immunology 38 (2020):289–313.

[334] Y.Zhang, W.Qin, and C.Wang, “Discovery of Post-Translational Modifications in Immunometabolism by Chemical Proteomics,” Current Opinion in Biotechnology 68 (2021):37–43.

[335] R.Gupta, M.Sahu, D.Srivastava, S.Tiwari, R. K.Ambasta, and P.Kumar, “Post-Translational Modifications: Regulators of Neurodegenerative Proteinopathies,” Ageing Research Reviews 68 (2021):101336.

[336] M.Hofweber and D.Dormann, “Friend or Foe-Post-Translational Modifications as Regulators of Phase Separation and RNP Granule Dynamics,” Journal of Biological Chemistry 294, no. 18 (2019):7137–7150.

[337] T. H.Kim, B.Tsang, R. M.Vernon, N. Sonenberg, L. E.Kay, and J. D.Forman-Kay, “Phospho-Dependent Phase Separation of FMRP and CAPRIN1 Recapitulates Regulation of Translation and Deadenylation,” Science 365, no. 6455 (2019):825–829.

[338] M. DKnoll and C.Wonodi, “Oxford-AstraZeneca COVID-19 Vaccine Efficacy,” Lancet 397, no. 10269 (2021):72–74.

[339] G.Li, Y.Liu, H.Hu, S.Yuan, L.Zhou, and X. Chen, “Evolution of Innovative Drug R&D in China,” Nature Reviews Drug Discovery 21, no. 8 (2022):553–554.

[340] P. SHegde and D. S. Chen, “Top 10 Challenges in Cancer Immunotherapy,” Immunity 52, no. 1 (2020):17–35.

[341] A. AGingrich and A. R. Kirane, “Novel Targets in Melanoma,” Surgical Oncology Clinics of North America 29, no. 3 (2020):467–483.

[342] X.Zeng, S.Zhu, W.Lu, et al., “Target Identification Among Known Drugs by Deep Learning From Heterogeneous Networks,” Chemical Science 11, no. 7 (2020):1775–1797.

[343] A.Raguram, S.Banskota, and D. R.Liu, “Therapeutic In Vivo Delivery of Gene Editing Agents,” Cell 185, no. 15 (2022):2806–2827.

[344] A. V.Anzalone, L. W.Koblan, and D. R.Liu, “Genome Editing With CRISPR-Cas Nucleases, Base Editors, Transposases and Prime Editors,” Nature Biotechnology 38, no. 7 (2020):824–844.

[345] G. ANewby and D. R. Liu, “In Vivo Somatic Cell Base Editing and Prime Editing,” Molecular Therapy 29, no. 11 (2021):3107–3124.

[346] J.Fares, M. Y.Fares, H. H.Khachfe, H. A.Salhab, and Y.Fares, “Molecular Principles of Metastasis: A Hallmark of Cancer Revisited,” Signal Transduction and Targeted Therapy 5, no. 1 (2020):28.

[347] K.Paunovska, D.Loughrey, and J. E.Dahlman, “Drug Delivery Systems for RNA Therapeutics,” Nature Reviews Genetics 23, no. 5 (2022):265–280.

[348] L. R.Baden, H. M.El Sahly, B.Essink, et al., “Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine,” New England Journal of Medicine 384, no. 5 (2021):403–416.

[349] D.Adams, A.Gonzalez-Duarte, W. D.O’Riordan, et al., “Patisiran, an RNAi Therapeutic, for Hereditary Transthyretin Amyloidosis,” New England Journal of Medicine 379, no. 1 (2018):11–21.

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