Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).
Google Scholar
Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the rosetta stone of therapy resistance. Cancer Cell 37, 471–484 (2020).
Google Scholar
Turner, K. M. et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543, 122–125 (2017).
Google Scholar
Calderaro, J. et al. Histological subtypes of hepatocellular carcinoma are related to gene mutations and molecular tumour classification. J. Hepatol. 67, 727–738 (2017).
Google Scholar
Ma, L. et al. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell 36, 418–430.e416 (2019).
Google Scholar
Luo, W. Nasopharyngeal carcinoma ecology theory: cancer as multidimensional spatiotemporal “unity of ecology and evolution” pathological ecosystem. Theranostics 13, 1607–1631 (2023).
Google Scholar
Martínez-Jiménez, F. et al. A compendium of mutational cancer driver genes. Nat. Rev. Cancer 20, 555–572 (2020).
Google Scholar
Park, J., Hsueh, P. C., Li, Z. & Ho, P. C. Microenvironment-driven metabolic adaptations guiding CD8(+) T cell anti-tumor immunity. Immunity 56, 32–42 (2023).
Google Scholar
Chen, X. & Song, E. The theory of tumor ecosystem. Cancer Commun. (Lond.) 42, 587–608 (2022).
Google Scholar
McCormack, V. A. & Boffetta, P. Today’s lifestyles, tomorrow’s cancers: trends in lifestyle risk factors for cancer in low- and middle-income countries. Ann. Oncol. 22, 2349–2357 (2011).
Google Scholar
Steck, S. E. & Murphy, E. A. Dietary patterns and cancer risk. Nat. Rev. Cancer 20, 125–138 (2020).
Google Scholar
Vineis, P. & Xun, W. The emerging epidemic of environmental cancers in developing countries. Ann. Oncol. 20, 205–212 (2009).
Google Scholar
Cullin, N. et al. Microbiome and cancer. Cancer Cell 39, 1317–1341 (2021).
Google Scholar
Galeano Niño, J. L. et al. Effect of the intratumoral microbiota on spatial and cellular heterogeneity in cancer. Nature 611, 810–817 (2022).
Google Scholar
van Tuijl, L. A. et al. Depression, anxiety, and the risk of cancer: an individual participant data meta-analysis. Cancer 129, 3287–3299 (2023).
Google Scholar
Johnston, E. E. & Rosenberg, A. R. Palliative care in adolescents and young adults with cancer. J. Clin. Oncol. 42, 755–763 (2024).
Google Scholar
Grassi, L. Psychiatric and psychosocial implications in cancer care: the agenda of psycho-oncology. Epidemiol. Psychiatr. Sci. 29, e89 (2020).
Google Scholar
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Google Scholar
Hanahan, D. Hallmarks of cancer: new dimensions. Cancer Discov. 12, 31–46 (2022).
Google Scholar
de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: From cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).
Google Scholar
Greaves, M. & Maley, C. C. Clonal evolution in cancer. Nature 481, 306–313 (2012).
Google Scholar
Werner, H. M. J., Mills, G. B. & Ram, P. T. Cancer Systems Biology: a peek into the future of patient care? Nat. Rev. Clin. Oncol. 11, 167–176 (2014).
Google Scholar
Gasperini, P. et al. Germline-somatic liaison dictates cancer subtypes via de novo steroid biosynthesis. Cancer Discov. 15, 2166–2184 (2025).
Google Scholar
Carter, H. et al. Interaction landscape of inherited polymorphisms with somatic events in cancer. Cancer Discov. 7, 410–423 (2017).
Google Scholar
Yang, D. et al. Association of BRCA1 and BRCA2 mutations with survival, chemotherapy sensitivity, and gene mutator phenotype in patients with ovarian cancer. JAMA 306, 1557–1565 (2011).
Google Scholar
Oliveira, E. A. et al. Epigenetic heritability of cell plasticity drives cancer drug resistance through a one-to-many genotype-to-phenotype paradigm. Cancer Res. 85, 2921–2938 (2025).
Google Scholar
Burdziak, C. et al. Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis. Science 380, eadd5327 (2023).
Google Scholar
Papathanasiou, S. et al. Heritable transcriptional defects from aberrations of nuclear architecture. Nature 619, 184–192 (2023).
Google Scholar
Marusyk, A. et al. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 514, 54–58 (2014).
Google Scholar
Cleary, A. S., Leonard, T. L., Gestl, S. A. & Gunther, E. J. Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 508, 113–117 (2014).
Google Scholar
Marshall, C. J., Vousden, K. H. & Phillips, D. H. Activation of c-Ha-ras-1 proto-oncogene by in vitro modification with a chemical carcinogen, benzo(a)pyrene diol-epoxide. Nature 310, 586–589 (1984).
Google Scholar
Cowell, J. K. Tumour suppressor genes. Ann. Oncol. 3, 693–698 (1992).
Google Scholar
Weinberg, R. A. Oncogenes and tumor suppressor genes. CA Cancer J. Clin. 44, 160–170 (1994).
Google Scholar
Voldborg, B. R., Damstrup, L., Spang-Thomsen, M. & Poulsen, H. S. Epidermal growth factor receptor (EGFR) and EGFR mutations, function and possible role in clinical trials. Ann. Oncol. 8, 1197–1206 (1997).
Google Scholar
Levantini, E., Maroni, G., Del Re, M. & Tenen, D. G. EGFR signaling pathway as therapeutic target in human cancers. Semin Cancer Biol. 85, 253–275 (2022).
Google Scholar
Hsu, W. H., Yang, J. C., Mok, T. S. & Loong, H. H. Overview of current systemic management of EGFR-mutant NSCLC. Ann. Oncol. 29, i3–i9 (2018).
Google Scholar
Huang, L., Guo, Z., Wang, F. & Fu, L. KRAS mutation: from undruggable to druggable in cancer. Signal Transduct. Target Ther. 6, 386 (2021).
Google Scholar
Liu, Y., Su, Z., Tavana, O. & Gu, W. Understanding the complexity of p53 in a new era of tumor suppression. Cancer Cell 42, 946–967 (2024).
Google Scholar
Wang, H., Guo, M., Wei, H. & Chen, Y. Targeting p53 pathways: mechanisms, structures, and advances in therapy. Signal Transduct. Target. Ther. 8, 92 (2023).
Google Scholar
Kim, J. et al. Wild-type p53 promotes cancer metabolic switch by inducing PUMA-dependent suppression of oxidative phosphorylation. Cancer Cell 35, 191–203.e198 (2019).
Google Scholar
Patocs, A. et al. Breast-cancer stromal cells with TP53 mutations and nodal metastases. N. Engl. J. Med. 357, 2543–2551 (2007).
Google Scholar
Baggiolini, A. et al. Developmental chromatin programs determine oncogenic competence in melanoma. Science 373, eabc1048 (2021).
Google Scholar
Grothey, A., Fakih, M. & Tabernero, J. Management of BRAF-mutant metastatic colorectal cancer: a review of treatment options and evidence-based guidelines. Ann. Oncol. 32, 959–967 (2021).
Google Scholar
Dibitetto, D., Widmer, C. A. & Rottenberg, S. PARPi, BRCA, and gaps: controversies and future research. Trends Cancer 10, 857–869 (2024).
Google Scholar
Turan, V. & Oktay, K. BRCA-related ATM-mediated DNA double-strand break repair and ovarian aging. Hum. Reprod. Update 26, 43–57 (2020).
Google Scholar
Pirozzi, C. J. & Yan, H. The implications of IDH mutations for cancer development and therapy. Nat. Rev. Clin. Oncol. 18, 645–661 (2021).
Google Scholar
Rudà, R. et al. IDH inhibition in gliomas: from preclinical models to clinical trials. Nat. Rev. Neurol. 20, 395–407 (2024).
Google Scholar
Brandner, S. et al. MGMT promoter methylation testing to predict overall survival in people with glioblastoma treated with temozolomide: a comprehensive meta-analysis based on a Cochrane Systematic Review. Neuro Oncol. 23, 1457–1469 (2021).
Google Scholar
Butler, M. et al. MGMT status as a clinical biomarker in glioblastoma. Trends Cancer 6, 380–391 (2020).
Google Scholar
Anderson, P., Aptsiauri, N., Ruiz-Cabello, F. & Garrido, F. HLA class I loss in colorectal cancer: implications for immune escape and immunotherapy. Cell Mol. Immunol. 18, 556–565 (2021).
Google Scholar
Fiorini, E. et al. MYC ecDNA promotes intratumour heterogeneity and plasticity in PDAC. Nature 640, 811–820 (2025).
Google Scholar
Hazini, A., Fisher, K. & Seymour, L. Deregulation of HLA-I in cancer and its central importance for immunotherapy. J. Immunother. Cancer 9, e002899 (2021).
Google Scholar
Quinton, R. J. et al. Whole-genome doubling confers unique genetic vulnerabilities on tumour cells. Nature 590, 492–497 (2021).
Google Scholar
Vittoria, M. A., Quinton, R. J. & Ganem, N. J. Whole-genome doubling in tissues and tumors. Trends Genet. 39, 954–967 (2023).
Google Scholar
Dentro, S. C. et al. Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell 184, 2239–2254.e2239 (2021).
Google Scholar
Reiter, J. G. et al. An analysis of genetic heterogeneity in untreated cancers. Nat. Rev. Cancer 19, 639–650 (2019).
Google Scholar
Johnson, K. C. et al. Single-cell multimodal glioma analyses identify epigenetic regulators of cellular plasticity and environmental stress response. Nat. Genet. 53, 1456–1468 (2021).
Google Scholar
Torres, C. M. et al. The linker histone H1.0 generates epigenetic and functional intratumor heterogeneity. Science 353, aaf1644 (2016).
Google Scholar
Laisné, M., Lupien, M. & Vallot, C. Epigenomic heterogeneity as a source of tumour evolution. Nat. Rev. Cancer 25, 7–26 (2025).
Google Scholar
Chaligne, R. et al. Epigenetic encoding, heritability and plasticity of glioma transcriptional cell states. Nat. Genet. 53, 1469–1479 (2021).
Google Scholar
Mattei, A. L., Bailly, N. & Meissner, A. DNA methylation: a historical perspective. Trends Genet. 38, 676–707 (2022).
Google Scholar
Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).
Google Scholar
Koch, A. et al. Analysis of DNA methylation in cancer: location revisited. Nat. Rev. Clin. Oncol. 15, 459–466 (2018).
Google Scholar
Kinslow, C. J. et al. MGMT promoter methylation predicts overall survival after chemotherapy for 1p/19q-codeleted gliomas. Clin. Cancer Res. 29, 4399–4407 (2023).
Google Scholar
Yamada, Y. et al. Targeting DNA methylation and B7-H3 in RB1-deficient and neuroendocrine prostate cancer. Sci. Transl. Med. 15, eadf6732 (2023).
Google Scholar
Liu, Z. et al. Single-cell chromatin accessibility analysis reveals the epigenetic basis and signature transcription factors for the molecular subtypes of colorectal cancers. Cancer Discov. 14, 1082–1105 (2024).
Google Scholar
Shvedunova, M. & Akhtar, A. Modulation of cellular processes by histone and non-histone protein acetylation. Nat. Rev. Mol. Cell Biol. 23, 329–349 (2022).
Google Scholar
Bilbrough, T., Piemontese, E. & Seitz, O. Dissecting the role of protein phosphorylation: a chemical biology toolbox. Chem. Soc. Rev. 51, 5691–5730 (2022).
Google Scholar
Dong, Y. et al. Phosphorylation of PHF2 by AMPK releases the repressive H3K9me2 and inhibits cancer metastasis. Signal Transduct. Target. Ther. 8, 95 (2023).
Google Scholar
Dewson, G., Eichhorn, P. J. A. & Komander, D. Deubiquitinases in cancer. Nat. Rev. Cancer 23, 842–862 (2023).
Google Scholar
Li, X. et al. CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression. Autophagy 17, 4323–4340 (2021).
Google Scholar
Lee, J. J. et al. ERα-associated translocations underlie oncogene amplifications in breast cancer. Nature 618, 1024–1032 (2023).
Google Scholar
Haidar, M. A. et al. p16INK4A and p15INK4B gene deletions in primary leukemias. Blood 86, 311–315 (1995).
Google Scholar
Porubsky, D. et al. Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders. Cell 185, 1986–2005.e1926 (2022).
Google Scholar
Gordon, D. J., Resio, B. & Pellman, D. Causes and consequences of aneuploidy in cancer. Nat. Rev. Genet. 13, 189–203 (2012).
Google Scholar
Garribba, L. et al. Short-term molecular consequences of chromosome mis-segregation for genome stability. Nat. Commun. 14, 1353 (2023).
Google Scholar
Hosea, R. et al. The two sides of chromosomal instability: drivers and brakes in cancer. Signal Transduct. Target. Ther. 9, 75 (2024).
Google Scholar
Rosswog, C. et al. Chromothripsis followed by circular recombination drives oncogene amplification in human cancer. Nat. Genet. 53, 1673–1685 (2021).
Google Scholar
Mariani, L. et al. Loss of heterozygosity 1p36 and 19q13 is a prognostic factor for overall survival in patients with diffuse WHO grade 2 gliomas treated without chemotherapy. J. Clin. Oncol. 24, 4758–4763 (2006).
Google Scholar
Chen, X. et al. Chromosomal instability as a driver of cancer progression. Nat. Rev. Genet. 26, 31–46 (2025).
Google Scholar
Dietlein, F. et al. Genome-wide analysis of somatic noncoding mutation patterns in cancer. Science 376, eabg5601 (2022).
Google Scholar
Bozic, I. et al. Accumulation of driver and passenger mutations during tumor progression. Proc. Natl. Acad. Sci. USA 107, 18545–18550 (2010).
Google Scholar
Kumar, S. et al. Passenger mutations in more than 2500 cancer genomes: overall molecular functional impact and consequences. Cell 180, 915–927.e916 (2020).
Google Scholar
McFarland, C. D. et al. Impact of deleterious passenger mutations on cancer progression. Proc. Natl. Acad. Sci. USA 110, 2910–2915 (2013).
Google Scholar
Damsky, W. E. & Bosenberg, M. Melanocytic nevi and melanoma: unraveling a complex relationship. Oncogene 36, 5771–5792 (2017).
Google Scholar
Núñez, F. J. et al. IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. Sci. Transl. Med. 11, eaaq1427 (2019).
Google Scholar
Wu, P. & Hu, Y. Z. PI3K/Akt/mTOR pathway inhibitors in cancer: a perspective on clinical progress. Curr. Med. Chem. 17, 4326–4341 (2010).
Google Scholar
Janku, F., Yap, T. A. & Meric-Bernstam, F. Targeting the PI3K pathway in cancer: are we making headway? Nat. Rev. Clin. Oncol. 15, 273–291 (2018).
Google Scholar
Mohamed, E. et al. PI3K/AKT/mTOR signaling pathway activity in IDH-mutant diffuse glioma and clinical implications. Neuro Oncol. 24, 1471–1481 (2022).
Google Scholar
Coussy, F. et al. Combination of PI3K and MEK inhibitors yields durable remission in PDX models of PIK3CA-mutated metaplastic breast cancers. J. Hematol. Oncol. 13, 13 (2020).
Google Scholar
Yamamoto, D. et al. Characterization of RNF43 frameshift mutations that drive Wnt ligand- and R-spondin-dependent colon cancer. J. Pathol. 257, 39–52 (2022).
Google Scholar
Zhao, H. et al. Wnt signaling in colorectal cancer: pathogenic role and therapeutic target. Mol. Cancer 21, 144 (2022).
Google Scholar
Ge, T. et al. Crosstalk between metabolic reprogramming and epigenetics in cancer: updates on mechanisms and therapeutic opportunities. Cancer Commun. 42, 1049–1082 (2022).
Google Scholar
Demicco, M., Liu, X.-Z., Leithner, K. & Fendt, S.-M. Metabolic heterogeneity in cancer. Nat. Metab. 6, 18–38 (2024).
Google Scholar
Patel, C. H., Leone, R. D., Horton, M. R. & Powell, J. D. Targeting metabolism to regulate immune responses in autoimmunity and cancer. Nat. Rev. Drug Discov. 18, 669–688 (2019).
Google Scholar
Fontana, F., Giannitti, G., Marchesi, S. & Limonta, P. The PI3K/Akt pathway and glucose metabolism: a dangerous liaison in cancer. Int. J. Biol. Sci. 20, 3113–3125 (2024).
Google Scholar
Hong, S. Y., Yu, F. X., Luo, Y. & Hagen, T. Oncogenic activation of the PI3K/Akt pathway promotes cellular glucose uptake by downregulating the expression of thioredoxin-interacting protein. Cell Signal 28, 377–383 (2016).
Google Scholar
Younes, M. et al. Wide expression of the human erythrocyte glucose transporter Glut1 in human cancers. Cancer Res. 56, 1164–1167 (1996).
Google Scholar
Commander, R. et al. Subpopulation targeting of pyruvate dehydrogenase and GLUT1 decouples metabolic heterogeneity during collective cancer cell invasion. Nat. Commun. 11, 1533 (2020).
Google Scholar
Borcherding, N. & Brestoff, J. R. The power and potential of mitochondria transfer. Nature 623, 283–291 (2023).
Google Scholar
Zhang, H. et al. Systematic investigation of mitochondrial transfer between cancer cells and T cells at single-cell resolution. Cancer Cell 41, 1788–1802.e1710 (2023).
Google Scholar
Baldwin, J. G. et al. Intercellular nanotube-mediated mitochondrial transfer enhances T cell metabolic fitness and antitumor efficacy. Cell 187, 6614–6630.e6621 (2024).
Google Scholar
Chen, C., Han, P. & Qing, Y. Metabolic heterogeneity in tumor microenvironment—a novel landmark for immunotherapy. Autoimmun. Rev. 23, 103579 (2024).
Google Scholar
Li, S. et al. Metabolism drives macrophage heterogeneity in the tumor microenvironment. Cell Rep. 39, 110609 (2022).
Google Scholar
Leone, R. D. & Powell, J. D. Metabolism of immune cells in cancer. Nat. Rev. Cancer 20, 516–531 (2020).
Google Scholar
Vandereyken, K., Sifrim, A., Thienpont, B. & Voet, T. Methods and applications for single-cell and spatial multi-omics. Nat. Rev. Genet. 24, 494–515 (2023).
Google Scholar
Sun, C. et al. Spatially resolved multi-omics highlights cell-specific metabolic remodeling and interactions in gastric cancer. Nat. Commun. 14, 2692 (2023).
Google Scholar
Parker, T. M. et al. Cell competition and tumor heterogeneity. Semin Cancer Biol. 63, 1–10 (2020).
Google Scholar
Cheung, K. J. & Horne-Badovinac, S. Collective migration modes in development, tissue repair and cancer. Nat. Rev. Mol. Cell Biol. 26, 741–758 (2025).
Google Scholar
Prasetyanti, P. R. & Medema, J. P. Intra-tumor heterogeneity from a cancer stem cell perspective. Mol. Cancer 16, 41 (2017).
Google Scholar
van Neerven, S. M. & Vermeulen, L. Cell competition in development, homeostasis and cancer. Nat. Rev. Mol. Cell Biol. 24, 221–236 (2023).
Google Scholar
Flanagan, D. J. et al. NOTUM from Apc-mutant cells biases clonal competition to initiate cancer. Nature 594, 430–435 (2021).
Google Scholar
Vilchez Mercedes, S. A. et al. Decoding leader cells in collective cancer invasion. Nat. Rev. Cancer 21, 592–604 (2021).
Google Scholar
Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J. & Werb, Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun. 11, 5120 (2020).
Google Scholar
Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).
Google Scholar
Gargiulo, G., Serresi, M. & Marine, J. C. Cell states in cancer: drivers, passengers, and trailers. Cancer Discov. 14, 610–614 (2024).
Google Scholar
Chen, J. et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488, 522–526 (2012).
Google Scholar
Dirkse, A. et al. Stem cell-associated heterogeneity in glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment. Nat. Commun. 10, 1787 (2019).
Google Scholar
Bocci, F. et al. Toward understanding cancer stem cell heterogeneity in the tumor microenvironment. Proc. Natl. Acad. Sci. USA 116, 148–157 (2019).
Google Scholar
Pan, G. et al. EMT-associated microRNAs and their roles in cancer stemness and drug resistance. Cancer Commun. 41, 199–217 (2021).
Google Scholar
McCabe, E. M. & Rasmussen, T. P. lncRNA involvement in cancer stem cell function and epithelial-mesenchymal transitions. Semin Cancer Biol. 75, 38–48 (2021).
Google Scholar
Gangoso, E. et al. Glioblastomas acquire myeloid-affiliated transcriptional programs via epigenetic immunoediting to elicit immune evasion. Cell 184, 2454–2470.e2426 (2021).
Google Scholar
Galassi, C., Chan, T. A., Vitale, I. & Galluzzi, L. The hallmarks of cancer immune evasion. Cancer Cell 42, 1825–1863 (2024).
Google Scholar
Robert, C. A decade of immune-checkpoint inhibitors in cancer therapy. Nat. Commun. 11, 3801 (2020).
Google Scholar
Herbst, R. S., Morgensztern, D. & Boshoff, C. The biology and management of non-small cell lung cancer. Nature 553, 446–454 (2018).
Google Scholar
Huang, M.-Y. et al. Combination therapy with PD-1/PD-L1 blockade in non-small cell lung cancer: strategies and mechanisms. Pharm. Ther. 219, 107694 (2021).
Google Scholar
Brahmer, J. R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
Google Scholar
Liu, X. et al. Immune checkpoint HLA-E:CD94-NKG2A mediates evasion of circulating tumor cells from NK cell surveillance. Cancer Cell 41, 272–287.e279 (2023).
Google Scholar
Dammeijer, F. et al. The PD-1/PD-L1-checkpoint restrains T cell immunity in tumor-draining lymph nodes. Cancer Cell 38, 685–700.e688 (2020).
Google Scholar
Li, D. et al. β2-Microglobulin maintains glioblastoma stem cells and induces M2-like polarization of tumor-associated macrophages. Cancer Res. 82, 3321–3334 (2022).
Google Scholar
Zhang, R. et al. PMN-MDSCs modulated by CCL20 from cancer cells promoted breast cancer cell stemness through CXCL2-CXCR2 pathway. Signal Transduct. Target. Ther. 8, 97 (2023).
Google Scholar
Rodrigues, J., Heinrich, M. A., Teixeira, L. M. & Prakash, J. 3D in vitro model (R)evolution: unveiling tumor-stroma interactions. Trends Cancer 7, 249–264 (2021).
Google Scholar
Zhao, Y. et al. Stromal cells in the tumor microenvironment: accomplices of tumor progression? Cell Death Dis. 14, 587 (2023).
Google Scholar
de Almeida, L. G. N. et al. Matrix metalloproteinases: from molecular mechanisms to physiology, pathophysiology, and pharmacology. Pharm. Rev. 74, 712–768 (2022).
Google Scholar
Wan, X. et al. FOSL2 promotes VEGF-independent angiogenesis by transcriptionally activating Wnt5a in breast cancer-associated fibroblasts. Theranostics 11, 4975–4991 (2021).
Google Scholar
Zhang, Z. et al. Cancer-associated fibroblasts-derived CXCL12 enhances immune escape of bladder cancer through inhibiting P62-mediated autophagic degradation of PDL1. J. Exp. Clin. Cancer Res. 42, 316 (2023).
Google Scholar
Zhong, W. et al. Human bone marrow-derived mesenchymal stem cells promote the growth and drug-resistance of diffuse large B-cell lymphoma by secreting IL-6 and elevating IL-17A levels. J. Exp. Clin. Cancer Res. 38, 73 (2019).
Google Scholar
Figueroa, J. et al. Exosomes from glioma-associated mesenchymal stem cells increase the tumorigenicity of glioma stem-like cells via transfer of miR-1587. Cancer Res. 77, 5808–5819 (2017).
Google Scholar
Mo, C. K. et al. Tumour evolution and microenvironment interactions in 2D and 3D space. Nature 634, 1178–1186 (2024).
Google Scholar
Tavernari, D. et al. Nongenetic evolution drives lung adenocarcinoma spatial heterogeneity and progression. Cancer Discov. 11, 1490–1507 (2021).
Google Scholar
Yuan, Z. et al. Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments. Mol. Cancer 22, 48 (2023).
Google Scholar
Fu, T. et al. Spatial architecture of the immune microenvironment orchestrates tumor immunity and therapeutic response. J. Hematol. Oncol. 14, 98 (2021).
Google Scholar
Zhang, J., Huang, D., Saw, P. E. & Song, E. Turning cold tumors hot: from molecular mechanisms to clinical applications. Trends Immunol. 43, 523–545 (2022).
Google Scholar
Wang, L. et al. Hot and cold tumors: Immunological features and the therapeutic strategies. MedComm 4, e343 (2023).
Google Scholar
Wu, B. et al. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct. Target. Ther. 9, 274 (2024).
Google Scholar
Castiglioni, A. et al. Combined PD-L1/TGFβ blockade allows expansion and differentiation of stem cell-like CD8 T cells in immune excluded tumors. Nat. Commun. 14, 4703 (2023).
Google Scholar
Arner, E. N. & Rathmell, J. C. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell 41, 421–433 (2023).
Google Scholar
Wu, Z. et al. OMA1 reprograms metabolism under hypoxia to promote colorectal cancer development. EMBO Rep. 22, e50827 (2021).
Google Scholar
Taylor, C. T. & Scholz, C. C. The effect of HIF on metabolism and immunity. Nat. Rev. Nephrol. 18, 573–587 (2022).
Google Scholar
Carmeliet, P. et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394, 485–490 (1998).
Google Scholar
Luo, H. et al. Signaling metabolite succinylacetone activates HIF-1α and promotes angiogenesis in GSTZ1-deficient hepatocellular carcinoma. JCI Insight 8, e164968 (2023).
Google Scholar
Chen, T. et al. WDR5 facilitates EMT and metastasis of CCA by increasing HIF-1α accumulation in Myc-dependent and independent pathways. Mol. Ther. 29, 2134–2150 (2021).
Google Scholar
Apte, R. S., Chen, D. S. & Ferrara, N. VEGF in signaling and disease: beyond discovery and development. Cell 176, 1248–1264 (2019).
Google Scholar
Eelen, G., Treps, L., Li, X. & Carmeliet, P. Basic and therapeutic aspects of angiogenesis updated. Circ. Res. 127, 310–329 (2020).
Google Scholar
Wu, Q. et al. Hypoxia-inducible factors: master regulators of hypoxic tumor immune escape. J. Hematol. Oncol. 15, 77 (2022).
Google Scholar
Wang, M. et al. Therapeutic blocking of VEGF binding to neuropilin-2 diminishes PD-L1 expression to activate antitumor immunity in prostate cancer. Sci. Transl. Med. 15, eade5855 (2023).
Google Scholar
Sharma, R. et al. Determinants of resistance to VEGF-TKI and immune checkpoint inhibitors in metastatic renal cell carcinoma. J. Exp. Clin. Cancer Res. 40, 186 (2021).
Google Scholar
Liu, S. et al. Metabolic reprogramming and therapeutic resistance in primary and metastatic breast cancer. Mol. Cancer 23, 261 (2024).
Google Scholar
Lin, J., Rao, D., Zhang, M. & Gao, Q. Metabolic reprogramming in the tumor microenvironment of liver cancer. J. Hematol. Oncol. 17, 6 (2024).
Google Scholar
Fendt, S. M. 100 years of the Warburg effect: a cancer metabolism endeavor. Cell 187, 3824–3828 (2024).
Google Scholar
Certo, M. et al. Lactate modulation of immune responses in inflammatory versus tumour microenvironments. Nat. Rev. Immunol. 21, 151–161 (2021).
Google Scholar
Finley, L. W. S. What is cancer metabolism? Cell 186, 1670–1688 (2023).
Google Scholar
Xia, L. et al. The cancer metabolic reprogramming and immune response. Mol. Cancer 20, 28 (2021).
Google Scholar
Liu, Y. et al. Metabolic reprogramming in tumor immune microenvironment: Impact on immune cell function and therapeutic implications. Cancer Lett. 597, 217076 (2024).
Google Scholar
Zhang, Y. et al. Mechanical forces in the tumor microenvironment: roles, pathways, and therapeutic approaches. J. Transl. Med. 23, 313 (2025).
Google Scholar
Swaminathan, V. & Gloerich, M. Decoding mechanical cues by molecular mechanotransduction. Curr. Opin. Cell Biol. 72, 72–80 (2021).
Google Scholar
Chaudhuri, O. et al. Effects of extracellular matrix viscoelasticity on cellular behaviour. Nature 584, 535–546 (2020).
Google Scholar
Karamanos, N. K. et al. Extracellular matrix-based cancer targeting. Trends Mol. Med. 27, 1000–1013 (2021).
Google Scholar
Naba, A. Mechanisms of assembly and remodelling of the extracellular matrix. Nat. Rev. Mol. Cell Biol. 25, 865–885 (2024).
Google Scholar
Malandrino, A., Mak, M., Kamm, R. D. & Moeendarbary, E. Complex mechanics of the heterogeneous extracellular matrix in cancer. Extrem. Mech. Lett. 21, 25–34 (2018).
Google Scholar
Liu, C. et al. Heterogeneous microenvironmental stiffness regulates pro-metastatic functions of breast cancer cells. Acta Biomater. 131, 326–340 (2021).
Google Scholar
Bareham, B., Dibble, M. & Parsons, M. Defining and modeling dynamic spatial heterogeneity within tumor microenvironments. Curr. Opin. Cell Biol. 90, 102422 (2024).
Google Scholar
Roy, R., Yang, J. & Moses, M. A. Matrix metalloproteinases as novel biomarkers and potential therapeutic targets in human cancer. J. Clin. Oncol. 27, 5287–5297 (2009).
Google Scholar
Liu, J. et al. Targeting matrix metalloproteinases by E3 ubiquitin ligases as a way to regulate the tumor microenvironment for cancer therapy. Semin. Cancer Biol. 86, 259–268 (2022).
Google Scholar
Chen, Y., McAndrews, K. M. & Kalluri, R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18, 792–804 (2021).
Google Scholar
Zhou, P. et al. Engineered extracellular vesicles for targeted reprogramming of cancer-associated fibroblasts to potentiate therapy of pancreatic cancer. Signal Transduct. Target. Ther. 9, 151 (2024).
Google Scholar
Ma, Z. et al. Interferon-dependent SLC14A1(+) cancer-associated fibroblasts promote cancer stemness via WNT5A in bladder cancer. Cancer Cell 40, 1550–1565.e1557 (2022).
Google Scholar
Nia, H. T. et al. Solid stress and elastic energy as measures of tumour mechanopathology. Nat. Biomed. Eng. 1, 0004 (2016).
Google Scholar
Seano, G. et al. Solid stress in brain tumours causes neuronal loss and neurological dysfunction and can be reversed by lithium. Nat. Biomed. Eng. 3, 230–245 (2019).
Google Scholar
Chauhan, V. P. et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell 26, 14–15 (2014).
Google Scholar
Rey, J. A. et al. Heterogeneous mechanical stress and interstitial fluid flow predictions derived from DCE-MRI for Rat U251N orthotopic gliomas. Ann. Biomed. Eng. 52, 3053–3066 (2024).
Google Scholar
Barbazán, J. & Vignjevic, D. M. Cancer associated fibroblasts: is the force the path to the dark side? Curr. Opin. Cell Biol. 56, 71–79 (2019).
Google Scholar
Zanotelli, M. R. et al. Energetic costs regulated by cell mechanics and confinement are predictive of migration path during decision-making. Nat. Commun. 10, 4185 (2019).
Google Scholar
Li, M., Xi, N., Wang, Y. C. & Liu, L. Q. Atomic force microscopy for revealing micro/nanoscale mechanics in tumor metastasis: from single cells to microenvironmental cues. Acta Pharm. Sin. 42, 323–339 (2021).
Google Scholar
Janesick, A. et al. High resolution mapping of the tumor microenvironment using integrated single-cell, spatial and in situ analysis. Nat. Commun. 14, 8353 (2023).
Google Scholar
Zhang, S. et al. The peritumor microenvironment: physics and immunity. Trends Cancer 9, 609–623 (2023).
Google Scholar
Wang, F. et al. Turning attention to tumor-host interface and focus on the peritumoral heterogeneity of glioblastoma. Nat. Commun. 15, 10885 (2024).
Google Scholar
Yang, Z. et al. YTHDF2 in peritumoral hepatocytes mediates chemotherapy-induced antitumor immune responses through CX3CL1-mediated CD8(+) T cell recruitment. Mol. Cancer 23, 186 (2024).
Google Scholar
Chin, S. M. et al. Functional graphene for peritumoral brain microenvironment modulation therapy in glioblastoma. Small 19, e2208227 (2023).
Google Scholar
Wang, L. et al. Unveiling novel cell clusters and biomarkers in glioblastoma and its peritumoral microenvironment at the single-cell perspective. J. Transl. Med. 22, 551 (2024).
Google Scholar
Losic, B. et al. Intratumoral heterogeneity and clonal evolution in liver cancer. Nat. Commun. 11, 291 (2020).
Google Scholar
Angelova, M. et al. Evolution of metastases in space and time under immune selection. Cell 175, 751–765.e716 (2018).
Google Scholar
Wang, Y. et al. Pre-metastatic niche: formation, characteristics and therapeutic implication. Signal Transduct. Target. Ther. 9, 236 (2024).
Google Scholar
Aversa, C. et al. Metastatic breast cancer subtypes and central nervous system metastases. Breast 23, 623–628 (2014).
Google Scholar
Pereira, A. A. L. et al. Association between KRAS mutation and lung metastasis in advanced colorectal cancer. Br. J. Cancer 112, 424–428 (2015).
Google Scholar
Halabi, S. et al. Meta-analysis evaluating the impact of site of metastasis on overall survival in men with castration-resistant prostate cancer. J. Clin. Oncol. 34, 1652–1659 (2016).
Google Scholar
Zhao, K. et al. Longitudinal and multisite sampling reveals mutational and copy number evolution in tumors during metastatic dissemination. Nat. Genet. 57, 1504–1511 (2025).
Google Scholar
Xiao, Y. & Yu, D. Tumor microenvironment as a therapeutic target in cancer. Pharm. Ther. 221, 107753 (2021).
Google Scholar
Chu, X. et al. Co-inhibition of TIGIT and PD-1/PD-L1 in cancer immunotherapy: mechanisms and clinical trials. Mol. Cancer 22, 93 (2023).
Google Scholar
Yi, M. et al. Combination strategies with PD-1/PD-L1 blockade: current advances and future directions. Mol. Cancer 21, 28 (2022).
Google Scholar
Schmid, S. et al. Organ-specific response to nivolumab in patients with non-small cell lung cancer (NSCLC). Cancer Immunol. Immunother. 67, 1825–1832 (2018).
Google Scholar
Patras, L., Shaashua, L., Matei, I. & Lyden, D. Immune determinants of the pre-metastatic niche. Cancer Cell 41, 546–572 (2023).
Google Scholar
Gong, Z. et al. Lung fibroblasts facilitate pre-metastatic niche formation by remodeling the local immune microenvironment. Immunity 55, 1483–1500.e1489 (2022).
Google Scholar
Jackett, K. N. et al. How the bone microenvironment shapes the pre-metastatic niche and metastasis. Nat. Cancer 5, 1800–1814 (2024).
Google Scholar
McGinnis, C. S. et al. The temporal progression of lung immune remodeling during breast cancer metastasis. Cancer Cell 42, 1018–1031.e1016 (2024).
Google Scholar
Fane, M. E. et al. Stromal changes in the aged lung induce an emergence from melanoma dormancy. Nature 606, 396–405 (2022).
Google Scholar
Catenacci, D. V. et al. Acquisition of portal venous circulating tumor cells from patients with pancreaticobiliary cancers by endoscopic ultrasound. Gastroenterology 149, 1794–1803.e1794 (2015).
Google Scholar
Link, J. M. et al. Ongoing replication stress tolerance and clonal T cell responses distinguish liver and lung recurrence and outcomes in pancreatic cancer. Nat. Cancer 6, 123–144 (2025).
Google Scholar
Zhang, W. et al. The bone microenvironment invigorates metastatic seeds for further dissemination. Cell 184, 2471–2486.e2420 (2021).
Google Scholar
Chen, H. N. et al. Genomic evolution and diverse models of systemic metastases in colorectal cancer. Gut 71, 322–332 (2022).
Google Scholar
Park, E. M. et al. Targeting the gut and tumor microbiota in cancer. Nat. Med. 28, 690–703 (2022).
Google Scholar
Carmody, R. N., Sarkar, A. & Reese, A. T. Gut microbiota through an evolutionary lens. Science 372, 462–463 (2021).
Google Scholar
Schneider, E., O’Riordan, K. J., Clarke, G. & Cryan, J. F. Feeding gut microbes to nourish the brain: unravelling the diet-microbiota-gut-brain axis. Nat. Metab. 6, 1454–1478 (2024).
Google Scholar
Aburto, M. R. & Cryan, J. F. Gastrointestinal and brain barriers: unlocking gates of communication across the microbiota-gut-brain axis. Nat. Rev. Gastroenterol. Hepatol. 21, 222–247 (2024).
Google Scholar
Liu, X., Chen, Y., Zhang, S. & Dong, L. Gut microbiota-mediated immunomodulation in tumor. J. Exp. Clin. Cancer Res. 40, 221 (2021).
Google Scholar
Battaglia, T. W. et al. A pan-cancer analysis of the microbiome in metastatic cancer. Cell 187, 2324–2335.e2319 (2024).
Google Scholar
Wong, C. C. & Yu, J. Gut microbiota in colorectal cancer development and therapy. Nat. Rev. Clin. Oncol. 20, 429–452 (2023).
Google Scholar
Qu, R. et al. Role of the gut microbiota and its metabolites in tumorigenesis or development of colorectal cancer. Adv. Sci. 10, e2205563 (2023).
Google Scholar
Lu, Y. et al. Intrahepatic microbial heterogeneity in multifocal hepatocellular carcinoma and its association with host genomic and transcriptomic alterations. Cancer Discov. 15, 1630–1648 (2025).
Google Scholar
Choi, E. & Bai, X. C. The activation mechanism of the insulin receptor: a structural perspective. Annu. Rev. Biochem. 92, 247–272 (2023).
Google Scholar
Wu, Q. et al. Cancer-associated adipocytes: key players in breast cancer progression. J. Hematol. Oncol. 12, 95 (2019).
Google Scholar
Altman, B. J., Stine, Z. E. & Dang, C. V. From Krebs to clinic: glutamine metabolism to cancer therapy. Nat. Rev. Cancer 16, 619–634 (2016).
Google Scholar
Saito, Y. et al. LLGL2 rescues nutrient stress by promoting leucine uptake in ER(+) breast cancer. Nature 569, 275–279 (2019).
Google Scholar
Sivanand, S. & Vander Heiden, M. G. Emerging roles for branched-chain amino acid metabolism in cancer. Cancer Cell 37, 147–156 (2020).
Google Scholar
Koundouros, N. & Poulogiannis, G. Reprogramming of fatty acid metabolism in cancer. Br. J. Cancer 122, 4–22 (2020).
Google Scholar
Hoy, A. J., Nagarajan, S. R. & Butler, L. M. Tumour fatty acid metabolism in the context of therapy resistance and obesity. Nat. Rev. Cancer 21, 753–766 (2021).
Google Scholar
Huang, B., Song, B. L. & Xu, C. Cholesterol metabolism in cancer: mechanisms and therapeutic opportunities. Nat. Metab. 2, 132–141 (2020).
Google Scholar
El-Kenawi, A. et al. Macrophage-derived cholesterol contributes to therapeutic resistance in prostate cancer. Cancer Res. 81, 5477–5490 (2021).
Google Scholar
Xiao, J. et al. 25-Hydroxycholesterol regulates lysosome AMP kinase activation and metabolic reprogramming to educate immunosuppressive macrophages. Immunity 57, 1087–1104.e1087 (2024).
Google Scholar
Cote, A. L., Munger, C. J. & Ringel, A. E. Emerging insights into the impact of systemic metabolic changes on tumor-immune interactions. Cell Rep. 44, 115234 (2025).
Google Scholar
Thai, A. A. et al. Lung cancer. Lancet 398, 535–554 (2021).
Google Scholar
van der Perk, M. E. M. et al. Interindividual variation in ovarian reserve after gonadotoxic treatment in female childhood cancer survivors—a genome-wide association study: results from PanCareLIFE. Fertil. Steril. 122, 514–524 (2024).
Google Scholar
Zhang, G. et al. Deficiency of cancer/testis antigen gene CT55 causes male infertility in humans and mice. Cell Death Differ. 30, 500–514 (2023).
Google Scholar
Hoffmann, J. P., Liu, J. A., Seddu, K. & Klein, S. L. Sex hormone signaling and regulation of immune function. Immunity 56, 2472–2491 (2023).
Google Scholar
Li, S. et al. Sex hormones and genetic variants in hormone metabolic pathways associated with the risk of colorectal cancer. Environ. Int. 137, 105543 (2020).
Google Scholar
Bernard, V., Young, J. & Binart, N. Prolactin—a pleiotropic factor in health and disease. Nat. Rev. Endocrinol. 15, 356–365 (2019).
Google Scholar
Chen, D. W. et al. Thyroid cancer. Lancet 401, 1531–1544 (2023).
Google Scholar
Boucai, L., Zafereo, M. & Cabanillas, M. E. Thyroid cancer: a review. JAMA 331, 425–435 (2024).
Google Scholar
Haddad, R. I. et al. Thyroid Carcinoma, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Canc. Netw. 20, 925–951 (2022).
Google Scholar
Melmed, S. et al. Clinical biology of the pituitary adenoma. Endocr. Rev. 43, 1003–1037 (2022).
Google Scholar
Müller, H. L. et al. Craniopharyngioma. Nat. Rev. Dis. Prim. 5, 75 (2019).
Google Scholar
Argilés, J. M., López-Soriano, F. J., Stemmler, B. & Busquets, S. Cancer-associated cachexia – understanding the tumour macroenvironment and microenvironment to improve management. Nat. Rev. Clin. Oncol. 20, 250–264 (2023).
Google Scholar
Koh, K. et al. Cancer-associated cachexia: bridging clinical findings with mechanistic insights in human studies. Cancer Discov. 15, 1543–1568 (2025).
Google Scholar
Ferrer, M. et al. Cachexia: a systemic consequence of progressive, unresolved disease. Cell 186, 1824–1845 (2023).
Google Scholar
McGovern, J. et al. Cancer cachexia: a nutritional or a systemic inflammatory syndrome? Br. J. Cancer 127, 379–382 (2022).
Google Scholar
Deretic, V. Autophagy in inflammation, infection, and immunometabolism. Immunity 54, 437–453 (2021).
Google Scholar
Pu, T., Sun, J., Ren, G. & Li, H. Neuro-immune crosstalk in cancer: mechanisms and therapeutic implications. Signal Transduct. Target. Ther. 10, 176 (2025).
Google Scholar
Jin, H. et al. A body-brain circuit that regulates body inflammatory responses. Nature 630, 695–703 (2024).
Google Scholar
Zhang, Y. et al. Hijacking of the nervous system in cancer: mechanism and therapeutic targets. Mol. Cancer 24, 44 (2025).
Google Scholar
Zheng, Y. et al. Mechanisms of neural infiltration-mediated tumor metabolic reprogramming impacting immunotherapy efficacy in non-small cell lung cancer. J. Exp. Clin. Cancer Res. 43, 284 (2024).
Google Scholar
Sammons, M. et al. Brain-body physiology: local, reflex, and central communication. Cell 187, 5877–5890 (2024).
Google Scholar
Hosang, L., Flügel, A. & Odoardi, F. Body-brain axis: orchestrating immune responses. Cell Res. 34, 757–758 (2024).
Google Scholar
Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019).
Google Scholar
Wu, T. et al. Neuro-cancer interactions shape glioma intratumoral heterogeneity. Adv. Sci. 12, e06694 (2025).
Google Scholar
Sigorski, D. & Iżycka-Świeszewska, E. Sympathetic nervous signaling dictates prostate cancer progression. Cell Death Discov. 8, 109 (2022).
Google Scholar
Zahalka, A. H. & Frenette, P. S. Nerves in cancer. Nat. Rev. Cancer 20, 143–157 (2020).
Google Scholar
Qiao, G. et al. Chronic adrenergic stress contributes to metabolic dysfunction and an exhausted phenotype in T cells in the tumor microenvironment. Cancer Immunol. Res. 9, 651–664 (2021).
Google Scholar
Li, T. et al. Cancer-associated fibroblasts foster a high-lactate microenvironment to drive perineural invasion in pancreatic cancer. Cancer Res. 85, 2199–2217 (2025).
Google Scholar
Li, J., Kang, R. & Tang, D. Cellular and molecular mechanisms of perineural invasion of pancreatic ductal adenocarcinoma. Cancer Commun. 41, 642–660 (2021).
Google Scholar
Wang, H. et al. Role of the nervous system in cancers: a review. Cell Death Discov. 7, 76 (2021).
Google Scholar
Zhang, S. Chemotherapy-induced peripheral neuropathy and rehabilitation: a review. Semin Oncol. 48, 193–207 (2021).
Google Scholar
Carey, A. R., Page, B. R. & Miller, N. Radiation-induced optic neuropathy: a review. Br. J. Ophthalmol. 107, 743–749 (2023).
Google Scholar
Silverman, D. A. et al. Cancer-associated neurogenesis and nerve-cancer cross-talk. Cancer Res. 81, 1431–1440 (2021).
Google Scholar
Cole, S. W. et al. Sympathetic nervous system regulation of the tumour microenvironment. Nat. Rev. Cancer 15, 563–572 (2015).
Google Scholar
Xie, H. et al. An immune-sympathetic neuron communication axis guides adipose tissue browning in cancer-associated cachexia. Proc. Natl. Acad. Sci. USA 119, e2112840119 (2022).
Google Scholar
Hu, J. et al. Crosstalk between the peripheral nervous system and breast cancer influences tumor progression. Biochim. Biophys. Acta Rev. Cancer 1877, 188828 (2022).
Google Scholar
Zhao, Z., Nelson, A. R., Betsholtz, C. & Zlokovic, B. V. Establishment and dysfunction of the blood-brain barrier. Cell 163, 1064–1078 (2015).
Google Scholar
Pfau, S. J. et al. Characteristics of blood-brain barrier heterogeneity between brain regions revealed by profiling vascular and perivascular cells. Nat. Neurosci. 27, 1892–1903 (2024).
Google Scholar
Mäe, M. A. et al. Single-cell analysis of blood-brain barrier response to pericyte loss. Circ. Res. 128, e46–e62 (2021).
Google Scholar
Song, L. L. et al. Exosomal delivery of rapamycin modulates blood-brain barrier penetration and VEGF axis in glioblastoma. J. Control Release 381, 113605 (2025).
Google Scholar
Parab, S. et al. Local angiogenic interplay of Vegfc/d and Vegfa controls brain region-specific emergence of fenestrated capillaries. eLife 12, e86066 (2023).
Google Scholar
Yan, J., Zhang, Z. & Shi, H. HIF-1 is involved in high glucose-induced paracellular permeability of brain endothelial cells. Cell Mol. Life Sci. 69, 115–128 (2012).
Google Scholar
Li, Y. et al. Macrophage-cancer hybrid membrane-camouflaged nanoplatforms for HIF-1α gene silencing-enhanced sonodynamic therapy of glioblastoma. ACS Appl. Mater. Interfaces 15, 31150–31158 (2023).
Google Scholar
Preininger, M. K., Zaytseva, D., Lin, J. M. & Kaufer, D. Blood-brain barrier dysfunction promotes astrocyte senescence through albumin-induced TGFβ signaling activation. Aging Cell 22, e13747 (2023).
Google Scholar
Steeg, P. S. The blood-tumour barrier in cancer biology and therapy. Nat. Rev. Clin. Oncol. 18, 696–714 (2021).
Google Scholar
Xie, Y. et al. Single-cell dissection of the human blood-brain barrier and glioma blood-tumor barrier. Neuron 112, 3089–3105.e3087 (2024).
Google Scholar
Cui, J. et al. Immune exosomes loading self-assembled nanomicelles traverse the blood-brain barrier for chemo-immunotherapy against glioblastoma. ACS Nano 17, 1464–1484 (2023).
Google Scholar
Arina, A., Gutiontov, S. I. & Weichselbaum, R. R. Radiotherapy and immunotherapy for cancer: from “systemic” to “multisite. Clin. Cancer Res. 26, 2777–2782 (2020).
Google Scholar
Pointer, K. B., Pitroda, S. P. & Weichselbaum, R. R. Radiotherapy and immunotherapy: open questions and future strategies. Trends Cancer 8, 9–20 (2022).
Google Scholar
Desai, K., McManus, J. M. & Sharifi, N. Hormonal therapy for prostate cancer. Endocr. Rev. 42, 354–373 (2021).
Google Scholar
Weng, Z. et al. Therapeutic roles of mesenchymal stem cell-derived extracellular vesicles in cancer. J. Hematol. Oncol. 14, 136 (2021).
Google Scholar
Dunbar, C. E. et al. Gene therapy comes of age. Science 359, eaan4672 (2018).
Google Scholar
Hirata, E. & Sahai, E. Tumor microenvironment and differential responses to therapy. Cold Spring Harb. Perspect. Med. 7, a026781 (2017).
Google Scholar
Han, G. Y. Q. et al. Ecological and evolutionary dynamics to design and improve ovarian cancer treatment. Clin. Transl. Med. 14, e70012 (2024).
Google Scholar
Wardill, H. R. et al. Cytokine-mediated blood brain barrier disruption as a conduit for cancer/chemotherapy-associated neurotoxicity and cognitive dysfunction. Int. J. Cancer 139, 2635–2645 (2016).
Google Scholar
Skurlova, M. et al. Chemobrain in blood cancers: How chemotherapeutics interfere with the brain’s structure and functionality, immune system, and metabolic functions. Med. Res. Rev. 44, 5–22 (2024).
Google Scholar
Park, Y. H. et al. Chemotherapy induces dynamic immune responses in breast cancers that impact treatment outcome. Nat. Commun. 11, 6175 (2020).
Google Scholar
Epstein, R. S. et al. Patient burden and real-world management of chemotherapy-induced myelosuppression: results from an online survey of patients with solid tumors. Adv. Ther. 37, 3606–3618 (2020).
Google Scholar
Jaye, K., Li, C. G. & Bhuyan, D. J. The complex interplay of gut microbiota with the five most common cancer types: From carcinogenesis to therapeutics to prognoses. Crit. Rev. Oncol. Hematol. 165, 103429 (2021).
Google Scholar
Hong, B. Y. et al. Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis. Microbiome 7, 66 (2019).
Google Scholar
Yu, Z. et al. Tissue fibrosis induced by radiotherapy: current understanding of the molecular mechanisms, diagnosis and therapeutic advances. J. Transl. Med. 21, 708 (2023).
Google Scholar
Iyizoba-Ebozue, Z. et al. Neurocognitive function following (chemo)radiotherapy for nasopharyngeal cancer and other head and neck cancers: a systematic review. Radiother. Oncol. 188, 109863 (2023).
Google Scholar
Morris, Z. S. et al. Proceedings of the National Cancer Institute Workshop on combining immunotherapy with radiotherapy: challenges and opportunities for clinical translation. Lancet Oncol. 26, e152–e170 (2025).
Google Scholar
Beckers, C., Pruschy, M. & Vetrugno, I. Tumor hypoxia and radiotherapy: a major driver of resistance even for novel radiotherapy modalities. Semin. Cancer Biol. 98, 19–30 (2024).
Google Scholar
Fletcher, K. & Johnson, D. B. Chronic immune-related adverse events arising from immune checkpoint inhibitors: an update. J. Immunother. Cancer 12, e008591 (2024).
Google Scholar
Taieb, J., Lapeyre-Prost, A., Laurent Puig, P. & Zaanan, A. Exploring the best treatment options for BRAF-mutant metastatic colon cancer. Br. J. Cancer 121, 434–442 (2019).
Google Scholar
Ambrosini, M. et al. BRAF + EGFR +/- MEK inhibitors after immune checkpoint inhibitors in BRAF V600E mutated and deficient mismatch repair or microsatellite instability high metastatic colorectal cancer. Eur. J. Cancer 210, 114290 (2024).
Google Scholar
Zhong, C. et al. CRISPR screens reveal convergent targeting strategies against evolutionarily distinct chemoresistance in cancer. Nat. Commun. 15, 5502 (2024).
Google Scholar
Singhal, A. et al. A classical epithelial state drives acute resistance to KRAS inhibition in pancreatic cancer. Cancer Discov. 14, 2122–2134 (2024).
Google Scholar
Hugaboom, M. B. et al. Presence of tertiary lymphoid structures and exhausted tissue-resident T cells determines clinical response to PD-1 blockade in renal cell carcinoma. Cancer Discov. 15, 948–968 (2025).
Google Scholar
Amisaki, M. et al. IL-33-activated ILC2s induce tertiary lymphoid structures in pancreatic cancer. Nature 638, 1076–1084 (2025).
Google Scholar
Gomes-Santos, I. L. et al. Exercise training improves tumor control by increasing CD8(+) T-cell infiltration via CXCR3 signaling and sensitizes breast cancer to immune checkpoint blockade. Cancer Immunol. Res. 9, 765–778 (2021).
Google Scholar
Matson, V. et al. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science 359, 104–108 (2018).
Google Scholar
Yadegar, A. et al. Fecal microbiota transplantation: current challenges and future landscapes. Clin. Microbiol. Rev. 37, e0006022 (2024).
Google Scholar
Zhao, W. et al. Fecal microbiota transplantation plus tislelizumab and fruquintinib in refractory microsatellite stable metastatic colorectal cancer: an open-label, single-arm, phase II trial (RENMIN-215). EClinicalMedicine 66, 102315 (2023).
Google Scholar
Routy, B. et al. Fecal microbiota transplantation plus anti-PD-1 immunotherapy in advanced melanoma: a phase I trial. Nat. Med. 29, 2121–2132 (2023).
Google Scholar
Yang, J. et al. Epigenetic regulation in the tumor microenvironment: molecular mechanisms and therapeutic targets. Signal Transduct. Target Ther. 8, 210 (2023).
Google Scholar
Del Mastro, L. et al. Fluorouracil and dose-dense adjuvant chemotherapy in patients with early-stage breast cancer (GIM2): end-of-study results from a randomised, phase 3 trial. Lancet Oncol. 23, 1571–1582 (2022).
Google Scholar
Gilbert, M. R. et al. A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro Oncol. 23, 468–477 (2021).
Google Scholar
Pfister, C. et al. Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin or gemcitabine and cisplatin as perioperative chemotherapy for patients with nonmetastatic muscle-invasive bladder cancer: results of the GETUG-AFU V05 VESPER Trial. J. Clin. Oncol. 40, 2013–2022 (2022).
Google Scholar
Nathanson, D. A. et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science 343, 72–76 (2014).
Google Scholar
Alkhatib, H. et al. Patient-specific signaling signatures predict optimal therapeutic combinations for triple negative breast cancer. Mol. Cancer 23, 17 (2024).
Google Scholar
Wittenzellner, K. et al. Label-free single-cell phenotyping to determine tumor cell heterogeneity in pancreatic cancer in real time. JCI Insight 10, e169105 (2025).
Google Scholar
Zhang, Y. et al. Digital twin models for predicting venetoclax and azacitidine-induced neutropenia in patients with acute myeloid leukemia. NPJ Digit. Med. 8, 596 (2025).
Google Scholar
Sadée, C. et al. Medical digital twins: enabling precision medicine and medical artificial intelligence. Lancet Digit. Health 7, 100864 (2025).
Google Scholar
Rao, A., Barkley, D., França, G. S. & Yanai, I. Exploring tissue architecture using spatial transcriptomics. Nature 596, 211–220 (2021).
Google Scholar
Liu, Y. et al. Conserved spatial subtypes and cellular neighborhoods of cancer-associated fibroblasts revealed by single-cell spatial multi-omics. Cancer Cell 43, 905–924.e906 (2025).
Google Scholar
Robinson, S. D. et al. Spatial biology—unravelling complexity within the glioblastoma microenvironment. Trends Mol. Med. 31, 846–859 (2025).
Google Scholar
Chen, C. et al. Engineering tumor spatial heterogeneity in vitro. Adv. Drug Deliv. Rev. 229, 115757 (2026).
Google Scholar
Valanarasu, J. M. J. et al. Multimodal AI generates virtual population for tumor microenvironment modeling. Cell 189, 386–400.e319 (2026).
Google Scholar

