REFERENCES

1. Dagogo-Jack I, Shaw AT. Tumour heterogeneity and resistance to cancer therapies. Nat Rev Clin Oncol. 2018;15:81-94.

2. Zhao T, Chiang ZD, Morriss JW, et al. Spatial genomics enables multi-modal study of clonal heterogeneity in tissues. Nature. 2022;601:85-91.

3. Erickson A, He M, Berglund E, et al. Spatially resolved clonal copy number alterations in benign and malignant tissue. Nature. 2022;608:360-7.

4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-74.

5. Ruiz-Casado A, Martín-Ruiz A, Pérez LM, Provencio M, Fiuza-Luces C, Lucia A. Exercise and the hallmarks of cancer. Trends Cancer. 2017;3:423-41.

6. Fouad YA, Aanei C. Revisiting the hallmarks of cancer. Am J Cancer Res. 2017;7:1016-36.

7. Zuo C, Zhu J, Zou J, Chen L. Unravelling tumour spatiotemporal heterogeneity using spatial multimodal data. Clin Transl Med. 2025;15:e70331.

8. Jia Q, Wang A, Yuan Y, Zhu B, Long H. Heterogeneity of the tumor immune microenvironment and its clinical relevance. Exp Hematol Oncol. 2022;11:24.

9. Zhu Y, Lee H, White S, et al. Global loss of promoter-enhancer connectivity and rebalancing of gene expression during early colorectal cancer carcinogenesis. Nat Cancer. 2024;5:1697-712.

10. Russo M, Siravegna G, Blaszkowsky LS, et al. Tumor heterogeneity and lesion-specific response to targeted therapy in colorectal cancer. Cancer Discov. 2016;6:147-53.

11. Le J, Dian Y, Zhao D, et al. Single-cell multi-omics in cancer immunotherapy: from tumor heterogeneity to personalized precision treatment. Mol Cancer. 2025;24:221.

12. McKinley ET, Sui Y, Al-Kofahi Y, et al. Optimized multiplex immunofluorescence single-cell analysis reveals tuft cell heterogeneity. JCI Insight. 2017;2:93487.

13. Nemes P, Knolhoff AM, Rubakhin SS, Sweedler JV. Metabolic differentiation of neuronal phenotypes by single-cell capillary electrophoresis-electrospray ionization-mass spectrometry. Anal Chem. 2011;83:6810-7.

14. Zong C, Lu S, Chapman AR, Xie XS. Genome-wide detection of single-nucleotide and copy-number variations of a single human cell. Science. 2012;338:1622-6.

15. Zheng GXY, Terry JM, Belgrader P, et al. Massively parallel digital transcriptional profiling of single cells. Nat Commun. 2017;8:14049.

16. Buenrostro JD, Wu B, Litzenburger UM, et al. Single-cell chromatin accessibility reveals principles of regulatory variation. Nature. 2015;523:486-90.

17. Giesen C, Wang HA, Schapiro D, et al. Highly multiplexed imaging of tumor tissues with subcellular resolution by mass cytometry. Nat Methods. 2014;11:417-22.

18. Cao J, Zheng Z, Sun D, et al. Decoder-seq enhances mRNA capture efficiency in spatial RNA sequencing. Nat Biotechnol. 2024;42:1735-46.

19. Unterauer EM, Shetab Boushehri S, Jevdokimenko K, et al. Spatial proteomics in neurons at single-protein resolution. Cell. 2024;187:1785-800.e16.

20. Klughammer J, Abravanel DL, Segerstolpe Å, et al. A multi-modal single-cell and spatial expression map of metastatic breast cancer biopsies across clinicopathological features. Nat Med. 2024;30:3236-49.

21. Wang R, Song S, Qin J, et al. Evolution of immune and stromal cell states and ecotypes during gastric adenocarcinoma progression. Cancer Cell. 2023;41:1407-26.e9.

22. Liu Y, Zhang Q, Xing B, et al. Immune phenotypic linkage between colorectal cancer and liver metastasis. Cancer Cell. 2022;40:424-37.e5.

23. Zhang Y, Wang S, Zhang J, et al. Elucidating minimal residual disease of paediatric B-cell acute lymphoblastic leukaemia by single-cell analysis. Nat Cell Biol. 2022;24:242-52.

24. Jamal-Hanjani M, Wilson GA, McGranahan N, et al.; TRACERx Consortium. Tracking the evolution of non-small-cell lung cancer. N Engl J Med. 2017;376:2109-21.

25. Lareau CA, Ludwig LS, Muus C, et al. Massively parallel single-cell mitochondrial DNA genotyping and chromatin profiling. Nat Biotechnol. 2021;39:451-61.

26. Lim ZF, Ma PC. Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy. J Hematol Oncol. 2019;12:134.

27. Marsolier J, Prompsy P, Durand A, et al. H3K27me3 conditions chemotolerance in triple-negative breast cancer. Nat Genet. 2022;54:459-68.

28. Rehman SK, Haynes J, Collignon E, et al. Colorectal cancer cells enter a diapause-like DTP state to survive chemotherapy. Cell. 2021;184:226-42.e21.

29. Dhimolea E, de Matos Simoes R, Kansara D, et al. An embryonic diapause-like adaptation with suppressed Myc activity enables tumor treatment persistence. Cancer Cell. 2021;39:240-56.e11.

30. Salemme V, Centonze G, Avalle L, et al. The role of tumor microenvironment in drug resistance: emerging technologies to unravel breast cancer heterogeneity. Front Oncol. 2023;13:1170264.

31. Ge R, Wang Z, Cheng L. Tumor microenvironment heterogeneity an important mediator of prostate cancer progression and therapeutic resistance. NPJ Precis Oncol. 2022;6:31.

32. Jo Y, Choi N, Kim K, Koo HJ, Choi J, Kim HN. Chemoresistance of cancer cells: requirements of tumor microenvironment-mimicking in vitro models in anti-cancer drug development. Theranostics. 2018;8:5259-75.

33. Turke AB, Zejnullahu K, Wu YL, et al. Preexistence and clonal selection of MET amplification in EGFR mutant NSCLC. Cancer Cell. 2010;17:77-88.

34. Cadot S, Valle C, Tosolini M, et al. Longitudinal CITE-Seq profiling of chronic lymphocytic leukemia during ibrutinib treatment: evolution of leukemic and immune cells at relapse. Biomark Res. 2020;8:72.

35. Robertson AG, Meghani K, Cooley LF, et al. Expression-based subtypes define pathologic response to neoadjuvant immune-checkpoint inhibitors in muscle-invasive bladder cancer. Nat Commun. 2023;14:2126.

36. Kats I, Simovic-Lorenz M, Schreiber HS, et al. Spatio-temporal transcriptomics of chromothriptic SHH-medulloblastoma identifies multiple genetic clones that resist treatment and drive relapse. Nat Commun. 2024;15:10370.

37. França GS, Baron M, King BR, et al. Cellular adaptation to cancer therapy along a resistance continuum. Nature. 2024;631:876-83.

38. Miao Y, Yang H, Levorse J, et al. Adaptive immune resistance emerges from tumor-initiating stem cells. Cell. 2019;177:1172-86.e14.

39. Derrien J, Gastineau S, Frigout A, et al. Acquired resistance to a GPRC5D-directed T-cell engager in multiple myeloma is mediated by genetic or epigenetic target inactivation. Nat Cancer. 2023;4:1536-43.

40. Lorenz C, Hillmer AM, Brägelmann J. Predicting the next move: tracking the complexity of lung cancer evolution and metastasis. Signal Transduct Target Ther. 2023;8:291.

41. Kikuchi H, Maishi N, Annan DA, et al. Chemotherapy-induced IL8 upregulates MDR1/ABCB1 in tumor blood vessels and results in unfavorable outcome. Cancer Res. 2020;80:2996-3008.

42. Quek C, Pratapa A, Bai X, et al. Single-cell spatial multiomics reveals tumor microenvironment vulnerabilities in cancer resistance to immunotherapy. Cell Rep. 2024;43:114392.

43. Agostini A, Guerriero I, Piro G, et al. Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer. J Transl Med. 2023;21:843.

44. Liu Y, Xun Z, Ma K, et al. Identification of a tumour immune barrier in the HCC microenvironment that determines the efficacy of immunotherapy. J Hepatol. 2023;78:770-82.

45. Zhou X, Han J, Zuo A, et al. THBS2 + cancer-associated fibroblasts promote EMT leading to oxaliplatin resistance via COL8A1-mediated PI3K/AKT activation in colorectal cancer. Mol Cancer. 2024;23:282.

46. Mori Y, Okimoto Y, Sakai H, et al. Targeting PDGF signaling of cancer-associated fibroblasts blocks feedback activation of HIF-1α and tumor progression of clear cell ovarian cancer. Cell Rep Med. 2024;5:101532.

47. Li X, Poire A, Jeong KJ, et al. C5aR1 inhibition reprograms tumor associated macrophages and reverses PARP inhibitor resistance in breast cancer. Nat Commun. 2024;15:4485.

48. Wan X, Xie B, Sun H, et al. Exosomes derived from M2 type tumor-associated macrophages promote osimertinib resistance in non-small cell lung cancer through MSTRG.292666.16-miR-6836-5p-MAPK8IP3 axis. Cancer Cell Int. 2022;22:83.

49. Zhang C, Zhou W, Xu H, et al. Cancer-associated fibroblasts promote EGFR-TKI resistance via the CTHRC1/glycolysis/H3K18la positive feedback loop. Oncogene. 2025;44:1400-14.

50. Lee CH, Minh Nguyen T, Lee Y, et al. Therapy-induced senescence (TIS) and SASP: the p53-mediated interplay in cancer progression and treatment. Int J Mol Sci. 2025;27:357.

51. Cao L, Li K, Li Q, Tong Q, Wang Y, Huang L. The controversial role of senescence-associated secretory phenotype (SASP) in cancer therapy. Mol Cancer. 2025;24:283.

52. Raynard C, Ma X, Huna A, et al. NF-κB-dependent secretome of senescent cells can trigger neuroendocrine transdifferentiation of breast cancer cells. Aging Cell. 2022;21:e13632.

53. Labrie M, Brugge JS, Mills GB, Zervantonakis IK. Therapy resistance: opportunities created by adaptive responses to targeted therapies in cancer. Nat Rev Cancer. 2022;22:323-39.

54. Tsimberidou AM. Targeted therapy in cancer. Cancer Chemother Pharmacol. 2015;76:1113-32.

55. Zhang Y, Yang C, Chen X, et al. Cancer therapy resistance from a spatial-omics perspective. Clin Transl Med. 2025;15:e70396.

56. Thress KS, Paweletz CP, Felip E, et al. Acquired EGFR C797S mutation mediates resistance to AZD9291 in non-small cell lung cancer harboring EGFR T790M. Nat Med. 2015;21:560-2.

57. Menon R, Müller J, Schneider P, et al. A novel EGFR(C797) variant detected in a pleural biopsy specimen from an osimertinib-treated patient using a comprehensive hybrid capture-based next-generation sequencing assay. J Thorac Oncol. 2016;11:e105-7.

58. Nishino M, Suda K, Kobayashi Y, et al. Effects of secondary EGFR mutations on resistance against upfront osimertinib in cells with EGFR-activating mutations in vitro. Lung Cancer. 2018;126:149-55.

59. Ercan D, Choi HG, Yun CH, et al. EGFR mutations and resistance to irreversible pyrimidine-based EGFR inhibitors. Clin Cancer Res. 2015;21:3913-23.

60. Yu HA, Tian SK, Drilon AE, et al. Acquired resistance of EGFR-mutant lung cancer to a T790M-specific EGFR inhibitor: emergence of a third mutation (C797S) in the EGFR tyrosine kinase domain. JAMA Oncol. 2015;1:982-4.

61. Ou SI, Cui J, Schrock AB, et al. Emergence of novel and dominant acquired EGFR solvent-front mutations at Gly796 (G796S/R) together with C797S/R and L792F/H mutations in one EGFR (L858R/T790M) NSCLC patient who progressed on osimertinib. Lung Cancer. 2017;108:228-31.

62. Klempner SJ, Mehta P, Schrock AB, Ali SM, Ou SI. Cis-oriented solvent-front EGFR G796S mutation in tissue and ctDNA in a patient progressing on osimertinib: a case report and review of the literature. Lung Cancer. 2017;8:241-7.

63. Zheng D, Hu M, Bai Y, et al. EGFR G796D mutation mediates resistance to osimertinib. Oncotarget. 2017;8:49671-9.

64. Yang Z, Yang N, Ou Q, et al. Investigating novel resistance mechanisms to third-generation EGFR tyrosine kinase inhibitor osimertinib in non-small cell lung cancer patients. Clin Cancer Res. 2018;24:3097-107.

65. Zhang Y, He B, Zhou D, Li M, Hu C. Newly emergent acquired EGFR exon 18 G724S mutation after resistance of a T790M specific EGFR inhibitor osimertinib in non-small-cell lung cancer: a case report. Onco Targets Ther. 2019;12:51-6.

66. Li J, Wang Z, Groen HJM, et al. Uncommon EGFR G724S mutations arise in non-small-cell lung cancer patients with acquired resistance to first-generation EGFR-TKIs. Lung Cancer. 2018;118:173-5.

67. Oztan A, Fischer S, Schrock AB, et al. Emergence of EGFR G724S mutation in EGFR-mutant lung adenocarcinoma post progression on osimertinib. Lung Cancer. 2017;111:84-7.

68. Nukaga S, Yasuda H, Tsuchihara K, et al. Amplification of EGFR wild-type alleles in non-small cell lung cancer cells confers acquired resistance to mutation-selective EGFR tyrosine kinase inhibitors. Cancer Res. 2017;77:2078-89.

69. Knebel FH, Bettoni F, Shimada AK, et al. Sequential liquid biopsies reveal dynamic alterations of EGFR driver mutations and indicate EGFR amplification as a new mechanism of resistance to osimertinib in NSCLC. Lung Cancer. 2017;108:238-41.

70. Kim S, Kim TM, Kim DW, et al. Heterogeneity of genetic changes associated with acquired crizotinib resistance in ALK-rearranged lung cancer. J Thorac Oncol. 2013;8:415-22.

71. Shi H, Hugo W, Kong X, et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014;4:80-93.

72. Fedorenko IV, Paraiso KH, Smalley KS. Acquired and intrinsic BRAF inhibitor resistance in BRAF V600E mutant melanoma. Biochem Pharmacol. 2011;82:201-9.

73. Kemper K, Krijgsman O, Cornelissen-Steijger P, et al. Intra- and inter-tumor heterogeneity in a vemurafenib-resistant melanoma patient and derived xenografts. EMBO Mol Med. 2015;7:1104-18.

74. Soverini S, Hochhaus A, Nicolini FE, et al. BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from an expert panel on behalf of European LeukemiaNet. Blood. 2011;118:1208-15.

75. Rossari F, Minutolo F, Orciuolo E. Past, present, and future of Bcr-Abl inhibitors: from chemical development to clinical efficacy. J Hematol Oncol. 2018;11:84.

76. Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res. 2013;19:2240-7.

77. Engelman JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 2007;316:1039-43.

78. Passaro A, Jänne PA, Mok T, Peters S. Overcoming therapy resistance in EGFR-mutant lung cancer. Nat Cancer. 2021;2:377-91.

79. Izumi M, Fujii M, Kobayashi IS, et al. Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer. Cell Death Dis. 2024;15:580.

80. Grosselin K, Durand A, Marsolier J, et al. High-throughput single-cell ChIP-seq identifies heterogeneity of chromatin states in breast cancer. Nat Genet. 2019;51:1060-6.

81. Lu KV, Chang JP, Parachoniak CA, et al. VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell. 2012;22:21-35.

82. Jun HJ, Acquaviva J, Chi D, et al. Acquired MET expression confers resistance to EGFR inhibition in a mouse model of glioblastoma multiforme. Oncogene. 2012;31:3039-50.

83. Jussila AR, Haensel D, Gaddam S, Oro AE. Acquisition of drug resistance in basal cell nevus syndrome tumors through basal to squamous cell carcinoma transition. J Invest Dermatol. 2024;144:1368-77.e6.

84. Li NY, Zhang W, Haensel D, et al. Basal-to-inflammatory transition and tumor resistance via crosstalk with a pro-inflammatory stromal niche. Nat Commun. 2024;15:8134.

85. Li Y, Xie T, Wang S, et al. Mechanism exploration and model construction for small cell transformation in EGFR-mutant lung adenocarcinomas. Signal Transduct Target Ther. 2024;9:261.

86. Guan A, Quek C. Single-cell multi-omics: insights into therapeutic innovations to advance treatment in cancer. Int J Mol Sci. 2025;26:2447.

87. Cosgrove PA, Bild AH, Dellinger TH, Badie B, Portnow J, Nath A. Single-cell transcriptomics sheds light on tumor evolution: perspectives from City of Hope’s Clinical Trial Teams. J Clin Med. 2024;13:7507.

88. Liu X, Peng T, Xu M, et al. Spatial multi-omics: deciphering technological landscape of integration of multi-omics and its applications. J Hematol Oncol. 2024;17:72.

89. Radfar P, Aboulkheyr Es H, Salomon R, et al. Single-cell analysis of circulating tumour cells: enabling technologies and clinical applications. Trends Biotechnol. 2022;40:1041-60.

90. Lei Y, Tang R, Xu J, et al. Applications of single-cell sequencing in cancer research: progress and perspectives. J Hematol Oncol. 2021;14:91.

91. Lee S, Kim G, Lee J, Lee AC, Kwon S. Mapping cancer biology in space: applications and perspectives on spatial omics for oncology. Mol Cancer. 2024;23:26.

92. Buenrostro JD, Giresi PG, Zaba LC, Chang HY, Greenleaf WJ. Transposition of native chromatin for fast and sensitive epigenomic profiling of open chromatin, DNA-binding proteins and nucleosome position. Nat Methods. 2013;10:1213-8.

93. Guo H, Zhu P, Wu X, Li X, Wen L, Tang F. Single-cell methylome landscapes of mouse embryonic stem cells and early embryos analyzed using reduced representation bisulfite sequencing. Genome Res. 2013;23:2126-35.

94. Smallwood SA, Lee HJ, Angermueller C, et al. Single-cell genome-wide bisulfite sequencing for assessing epigenetic heterogeneity. Nat Methods. 2014;11:817-20.

95. Farlik M, Sheffield NC, Nuzzo A, et al. Single-cell DNA methylome sequencing and bioinformatic inference of epigenomic cell-state dynamics. Cell Rep. 2015;10:1386-97.

96. Shareef SJ, Bevill SM, Raman AT, et al. Extended-representation bisulfite sequencing of gene regulatory elements in multiplexed samples and single cells. Nat Biotechnol. 2021;39:1086-94.

97. Han L, Wu HJ, Zhu H, et al. Bisulfite-independent analysis of CpG island methylation enables genome-scale stratification of single cells. Nucleic Acids Res. 2017;45:e77.

98. Rotem A, Ram O, Shoresh N, et al. Single-cell ChIP-seq reveals cell subpopulations defined by chromatin state. Nat Biotechnol. 2015;33:1165-72.

99. Bartosovic M, Kabbe M, Castelo-Branco G. Single-cell CUT&Tag profiles histone modifications and transcription factors in complex tissues. Nat Biotechnol. 2021;39:825-35.

100. Bartosovic M, Castelo-Branco G. Multimodal chromatin profiling using nanobody-based single-cell CUT&Tag. Nat Biotechnol. 2023;41:794-805.

101. Harpaz N, Mittelman T, Beresh O, et al. Single-cell epigenetic analysis reveals principles of chromatin states in H3.3-K27M gliomas. Mol Cell. 2022;82:2696-713.e9.

102. Xiong H, Wang Q, Li CC, He A. Single-cell joint profiling of multiple epigenetic proteins and gene transcription. Sci Adv. 2024;10:eadi3664.

103. Lochs SJA, van der Weide RH, de Luca KL, et al. Combinatorial single-cell profiling of major chromatin types with MAbID. Nat Methods. 2024;21:72-82.

104. Stoeckius M, Hafemeister C, Stephenson W, et al. Simultaneous epitope and transcriptome measurement in single cells. Nat Methods. 2017;14:865-8.

105. Budnik B, Levy E, Harmange G, Slavov N. SCoPE-MS: mass spectrometry of single mammalian cells quantifies proteome heterogeneity during cell differentiation. Genome Biol. 2018;19:161.

106. Chen X, Sun M, Yang Z. Single cell mass spectrometry analysis of drug-resistant cancer cells: Metabolomics studies of synergetic effect of combinational treatment. Anal Chim Acta. 2022;1201:339621.

107. Zhu G, Zhang W, Zhao Y, et al. Single-cell mass spectrometry studies of secondary drug resistance of tumor cells. Anal Chem. 2025;97:337-44.

108. Baysoy A, Bai Z, Satija R, Fan R. The technological landscape and applications of single-cell multi-omics. Nat Rev Mol Cell Biol. 2023;24:695-713.

109. Williams CG, Lee HJ, Asatsuma T, Vento-Tormo R, Haque A. An introduction to spatial transcriptomics for biomedical research. Genome Med. 2022;14:68.

110. Merritt CR, Ong GT, Church SE, et al. Multiplex digital spatial profiling of proteins and RNA in fixed tissue. Nat Biotechnol. 2020;38:586-99.

111. Shiau C, Cao J, Gong D, et al. Spatially resolved analysis of pancreatic cancer identifies therapy-associated remodeling of the tumor microenvironment. Nat Genet. 2024;56:2466-78.

112. Khafizov R, Piazza E, Cui Y, et al. Sub-cellular imaging of the entire protein-coding human transcriptome (18933-plex) on FFPE tissue using spatial molecular imaging. bioRxiv. 2024.

113. Deng Y, Bartosovic M, Ma S, et al. Spatial profiling of chromatin accessibility in mouse and human tissues. Nature. 2022;609:375-83.

114. Carraro C, Bonaguro L, Srinivasa R, et al. Chromatin accessibility profiling of targeted cell populations with laser capture microdissection coupled to ATAC-seq. Cell Rep Methods. 2023;3:100598.

115. Llorens-Bobadilla E, Zamboni M, Marklund M, et al. Solid-phase capture and profiling of open chromatin by spatial ATAC. Nat Biotechnol. 2023;41:1085-8.

116. Guo P, Chen Y, Mao L, et al. Spatial profiling of chromatin accessibility in formalin-fixed paraffin-embedded tissues. Nat Commun. 2025;16:5945.

117. Deng Y, Bartosovic M, Kukanja P, et al. Spatial-CUT&Tag: spatially resolved chromatin modification profiling at the cellular level. Science. 2022;375:681-6.

118. Liu Y, DiStasio M, Su G, et al. High-plex protein and whole transcriptome co-mapping at cellular resolution with spatial CITE-seq. Nat Biotechnol. 2023;41:1405-9.

119. Goltsev Y, Samusik N, Kennedy-Darling J, et al. Deep profiling of mouse splenic architecture with CODEX multiplexed imaging. Cell. 2018;174:968-81.e15.

120. Fan J, Lu F, Qin T, et al. Multiomic analysis of cervical squamous cell carcinoma identifies cellular ecosystems with biological and clinical relevance. Nat Genet. 2023;55:2175-88.

121. Ding J, Ahangari F, Espinoza CR, et al. Integrating multiomics longitudinal data to reconstruct networks underlying lung development. Am J Physiol Lung Cell Mol Physiol. 2019;317:L556-68.

122. Dilillo M, Ait-Belkacem R, Esteve C, et al. Ultra-high mass resolution MALDI imaging mass spectrometry of proteins and metabolites in a mouse model of glioblastoma. Sci Rep. 2017;7:603.

123. Zhu X, Xu T, Peng C, Wu S. Advances in MALDI mass spectrometry imaging single cell and tissues. Front Chem. 2021;9:782432.

124. Miki A, Katagi M, Kamata T, et al. MALDI-TOF and MALDI-FTICR imaging mass spectrometry of methamphetamine incorporated into hair. J Mass Spectrom. 2011;46:411-6.

125. Navin N, Kendall J, Troge J, et al. Tumour evolution inferred by single-cell sequencing. Nature. 2011;472:90-4.

126. Tang F, Barbacioru C, Wang Y, et al. mRNA-Seq whole-transcriptome analysis of a single cell. Nat Methods. 2009;6:377-82.

127. Bandura DR, Baranov VI, Ornatsky OI, et al. Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. Anal Chem. 2009;81:6813-22.

128. Lapainis T, Rubakhin SS, Sweedler JV. Capillary electrophoresis with electrospray ionization mass spectrometric detection for single-cell metabolomics. Anal Chem. 2009;81:5858-64.

129. Kim CW, Park H, Kim D, Seong Y, Kwon M, Kim J. CluVar: clustering of variants using autoencoder for inferring cancer subclones from single cell RNA sequencing data. Brief Bioinform. 2025;26:bbaf603.

130. Luo H, Hussain A, Abbas M, et al. Droplet-based single-cell RNA sequencing: decoding cellular heterogeneity for breakthroughs in cancer, reproduction, and beyond. J Transl Med. 2025;23:1091.

131. Jovic D, Liang X, Zeng H, Lin L, Xu F, Luo Y. Single-cell RNA sequencing technologies and applications: a brief overview. Clin Transl Med. 2022;12:e694.

132. Jerby-Arnon L, Shah P, Cuoco MS, et al. A cancer cell program promotes T cell exclusion and resistance to checkpoint blockade. Cell. 2018;175:984-97.e24.

133. Schnepp PM, Ahmed A, Escara-Wilke J, et al. Transcription factor network analysis based on single cell RNA-seq identifies that Trichostatin-a reverses docetaxel resistance in prostate Cancer. BMC Cancer. 2021;21:1316.

134. Taavitsainen S, Engedal N, Cao S, et al. Single-cell ATAC and RNA sequencing reveal pre-existing and persistent cells associated with prostate cancer relapse. Nat Commun. 2021;12:5307.

135. Satpathy AT, Granja JM, Yost KE, et al. Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat Biotechnol. 2019;37:925-36.

136. Wang L, Jung J, Babikir H, et al. A single-cell atlas of glioblastoma evolution under therapy reveals cell-intrinsic and cell-extrinsic therapeutic targets. Nat Cancer. 2022;3:1534-52.

137. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357:eaal2380.

138. Laisné M, Lupien M, Vallot C. Epigenomic heterogeneity as a source of tumour evolution. Nat Rev Cancer. 2025;25:7-26.

139. Wu SJ, Furlan SN, Mihalas AB, et al. Single-cell CUT&Tag analysis of chromatin modifications in differentiation and tumor progression. Nat Biotechnol. 2021;39:819-24.

140. Pombo Antunes AR, Scheyltjens I, Lodi F, et al. Single-cell profiling of myeloid cells in glioblastoma across species and disease stage reveals macrophage competition and specialization. Nat Neurosci. 2021;24:595-610.

141. Tian M, Cheuk AT, Wei JS, et al. An optimized bicistronic chimeric antigen receptor against GPC2 or CD276 overcomes heterogeneous expression in neuroblastoma. J Clin Invest. 2022;132:e155621.

142. Chen X, Peng Z, Yang Z. Metabolomics studies of cell-cell interactions using single cell mass spectrometry combined with fluorescence microscopy. Chem Sci. 2022;13:6687-95.

143. Sun M, Chen X, Yang Z. Single cell mass spectrometry studies reveal metabolomic features and potential mechanisms of drug-resistant cancer cell lines. Anal Chim Acta. 2022;1206:339761.

144. Weinstein JA, Regev A, Zhang F. DNA microscopy: optics-free spatio-genetic imaging by a stand-alone chemical reaction. Cell. 2019;178:229-41.e16.

145. Stickels RR, Murray E, Kumar P, et al. Highly sensitive spatial transcriptomics at near-cellular resolution with Slide-seqV2. Nat Biotechnol. 2021;39:313-9.

146. Srivatsan SR, Regier MC, Barkan E, et al. Embryo-scale, single-cell spatial transcriptomics. Science. 2021;373:111-7.

147. Ren J, Zhou H, Zeng H, et al. Spatiotemporally resolved transcriptomics reveals the subcellular RNA kinetic landscape. Nat Methods. 2023;20:695-705.

148. McKellar DW, Mantri M, Hinchman MM, et al. Spatial mapping of the total transcriptome by in situ polyadenylation. Nat Biotechnol. 2023;41:513-20.

149. Eng CHL, Lawson M, Zhu Q, et al. Transcriptome-scale super-resolved imaging in tissues by RNA seqFISH. Nature. 2019;568:235-9.

150. Codeluppi S, Borm LE, Zeisel A, et al. Spatial organization of the somatosensory cortex revealed by osmFISH. Nat Methods. 2018;15:932-5.

151. Chen A, Liao S, Cheng M, et al. Spatiotemporal transcriptomic atlas of mouse organogenesis using DNA nanoball-patterned arrays. Cell. 2022;185:1777-92.e21.

152. Andersson A, Larsson L, Stenbeck L, et al. Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions. Nat Commun. 2021;12:6012.

153. Zuo C, Zhang Y, Cao C, Feng J, Jiao M, Chen L. Elucidating tumor heterogeneity from spatially resolved transcriptomics data by multi-view graph collaborative learning. Nat Commun. 2022;13:5962.

154. Maleki EH, Bahrami AR, Matin MM. Cancer cell cycle heterogeneity as a critical determinant of therapeutic resistance. Genes Dis. 2024;11:189-204.

155. Jiang F, Zhou X, Qian Y, et al. Simultaneous profiling of spatial gene expression and chromatin accessibility during mouse brain development. Nat Methods. 2023;20:1048-57.

156. Lu T, Ang CE, Zhuang X. Spatially resolved epigenomic profiling of single cells in complex tissues. Cell. 2023;186:2275-9.

157. Zhang D, Deng Y, Kukanja P, et al. Spatial epigenome-transcriptome co-profiling of mammalian tissues. Nature. 2023;616:113-22.

158. Vickovic S, Lötstedt B, Klughammer J, et al. SM-Omics is an automated platform for high-throughput spatial multi-omics. Nat Commun. 2022;13:795.

159. Saka SK, Wang Y, Kishi JY, et al. Immuno-SABER enables highly multiplexed and amplified protein imaging in tissues. Nat Biotechnol. 2019;37:1080-90.

160. Rosenberger FA, Thielert M, Strauss MT, et al. Spatial single-cell mass spectrometry defines zonation of the hepatocyte proteome. Nat Methods. 2023;20:1530-6.

161. Radtke AJ, Kandov E, Lowekamp B, et al. IBEX: a versatile multiplex optical imaging approach for deep phenotyping and spatial analysis of cells in complex tissues. Proc Natl Acad Sci U S A. 2020;117:33455-65.

162. Mund A, Coscia F, Kriston A, et al. Deep visual proteomics defines single-cell identity and heterogeneity. Nat Biotechnol. 2022;40:1231-40.

163. Liu Y, Yang M, Deng Y, et al. High-spatial-resolution multi-omics sequencing via deterministic barcoding in tissue. Cell. 2020;183:1665-81.e18.

164. Liu X, Mao D, Song Y, et al. Computer-aided design of reversible hybridization chain reaction (CAD-HCR) enables multiplexed single-cell spatial proteomics imaging. Sci Adv. 2022;8:eabk0133.

165. Kuett L, Catena R, Özcan A, et al.; Cancer Grand Challenges IMAXT Consortium. Three-dimensional imaging mass cytometry for highly multiplexed molecular and cellular mapping of tissues and the tumor microenvironment. Nat Cancer. 2022;3:122-33.

166. Kinkhabwala A, Herbel C, Pankratz J, et al. MACSima imaging cyclic staining (MICS) technology reveals combinatorial target pairs for CAR T cell treatment of solid tumors. Sci Rep. 2022;12:1911.

167. Gut G, Herrmann MD, Pelkmans L. Multiplexed protein maps link subcellular organization to cellular states. Science. 2018;361:eaar7042.

168. Gessel MM, Norris JL, Caprioli RM. MALDI imaging mass spectrometry: spatial molecular analysis to enable a new age of discovery. J Proteomics. 2014;107:71-82.

169. Eisenstein M. Seven technologies to watch in 2022. Nature. 2022;601:658-61.

170. Dezem FS, Arjumand W, DuBose H, Morosini NS, Plummer J. Spatially resolved single-cell omics: methods, challenges, and future perspectives. Annu Rev Biomed Data Sci. 2024;7:131-53.

171. Alexandrov T, Saez-Rodriguez J, Saka SK. Enablers and challenges of spatial omics, a melting pot of technologies. Mol Syst Biol. 2023;19:e10571.

172. Marx V. Method of the year: spatially resolved transcriptomics. Nat Methods. 2021;18:9-14.

173. Kiviaho A, Eerola SK, Kallio HML, et al. Single cell and spatial transcriptomics highlight the interaction of club-like cells with immunosuppressive myeloid cells in prostate cancer. Nat Commun. 2024;15:9949.

174. Romero R, Chu T, González Robles TJ, et al. The neuroendocrine transition in prostate cancer is dynamic and dependent on ASCL1. Nat Cancer. 2024;5:1641-59.

175. Rubinstein JC, Domanskyi S, Sheridan TB, et al. Spatiotemporal profiling defines persistence and resistance dynamics during targeted treatment of melanoma. Cancer Res. 2025;85:987-1002.

176. Kulasinghe A, Monkman J, Shah ET, Matigian N, Adams MN, O’Byrne K. Spatial profiling identifies prognostic features of response to adjuvant therapy in triple negative breast cancer (TNBC). Front Oncol. 2021;11:798296.

177. Li Z, Metzger Filho O, Viale G, et al. HER2 heterogeneity and treatment response-associated profiles in HER2-positive breast cancer in the NCT02326974 clinical trial. J Clin Invest. 2024;134:e176454.

178. Gong D, Arbesfeld-Qiu JM, Perrault E, Bae JW, Hwang WL. Spatial oncology: translating contextual biology to the clinic. Cancer Cell. 2024;42:1653-75.

179. Bouchard G, Zhang W, Ilerten I, et al. A quantitative spatial cell-cell colocalizations framework enabling comparisons between in vitro assembloids and pathological specimens. Nat Commun. 2025;16:1392.

180. Jhaveri N, Ben Cheikh B, Nikulina N, et al. Mapping the spatial proteome of head and neck tumors: key immune mediators and metabolic determinants in the tumor microenvironment. GEN Biotechnol. 2023;2:418-34.

181. Planque M, Igelmann S, Ferreira Campos AM, Fendt SM. Spatial metabolomics principles and application to cancer research. Curr Opin Chem Biol. 2023;76:102362.

182. Wang J, Sun N, Kunzke T, et al. Metabolic heterogeneity affects trastuzumab response and survival in HER2-positive advanced gastric cancer. Br J Cancer. 2024;130:1036-45.

183. Shen J, Sun N, Zens P, et al. Spatial metabolomics for evaluating response to neoadjuvant therapy in non-small cell lung cancer patients. Cancer Commun. 2022;42:517-35.

184. Ji L, Wang D, Zhuo G, et al. Spatial metabolomics and transcriptomics reveal metabolic reprogramming and cellular interactions in nasopharyngeal carcinoma with high PD-1 expression and therapeutic response. Theranostics. 2025;15:3035-54.

185. Carbone C, De Luca R, Puca E, et al. Antibody-based delivery of interleukin-2 modulates the immunosuppressive tumor microenvironment and achieves cure in pancreatic ductal adenocarcinoma syngeneic mice. J Exp Clin Cancer Res. 2025;44:7.

186. Zhang KM, Zhao DC, Li ZY, et al. Inactivated cGAS-STING signaling facilitates endocrine resistance by forming a positive feedback loop with AKT kinase in ER+HER2- breast cancer. Adv Sci. 2024;11:e2403592.

187. Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al.; CheckMate 067 Investigators. Final, 10-year outcomes with nivolumab plus ipilimumab in advanced melanoma. N Engl J Med. 2025;392:11-22.

188. Caputo TM, Barisciano G, Mulè C, et al. Development of high-loading trastuzumab PLGA nanoparticles: a powerful tool against HER2 positive breast cancer cells. Int J Nanomedicine. 2023;18:6999-7020.

189. Ahn M, Kim T, Bonanno L, et al. 2O: SAVANNAH: Savolitinib (savo) + osimertinib (osi) in patients (pts) with EGFRm advanced NSCLC and METoverexpression (OverExp) and/or amplification (Amp) following progressive disease (PD) on osi. J Thorac Oncol. 2025;20:S4-5.

190. Lu S, Wang J, Yang N, et al.; SACHI Study Group. Savolitinib plus osimertinib versus chemotherapy for advanced, EGFR mutation-positive, MET-amplified non-small-cell lung cancer in China (SACHI): interim analysis of a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2026;407:375-87.

191. Deblois G, Tonekaboni SAM, Grillo G, et al. Epigenetic switch-induced viral mimicry evasion in chemotherapy-resistant breast cancer. Cancer Discov. 2020;10:1312-29.

192. Gini B, Thomas N, Blakely CM. Impact of concurrent genomic alterations in epidermal growth factor receptor (EGFR)-mutated lung cancer. J Thorac Dis. 2020;12:2883-95.

193. Liu Y, Li Y, Ou Q, et al. Acquired EGFR L718V mutation mediates resistance to osimertinib in non-small cell lung cancer but retains sensitivity to afatinib. Lung Cancer. 2018;118:1-5.

194. Choi YR, Kang EH, Kim S, Park SY, Han JY, Lee Y. Single targeting of MET in EGFR-mutated and MET-amplified non-small cell lung cancer. Br J Cancer. 2023;128:2186-96.

195. Rosen EY, Won HH, Zheng Y, et al. The evolution of RET inhibitor resistance in RET-driven lung and thyroid cancers. Nat Commun. 2022;13:1450.

196. Mo S, Tang P, Luo W, et al. Patient-derived organoids from colorectal cancer with paired liver metastasis reveal tumor heterogeneity and predict response to chemotherapy. Adv Sci. 2022;9:e2204097.

197. Saeki S, Kumegawa K, Takahashi Y, et al. Transcriptomic intratumor heterogeneity of breast cancer patient-derived organoids may reflect the unique biological features of the tumor of origin. Breast Cancer Res. 2023;25:21.

198. Um JH, Zheng Y, Mao Q, et al. Genomic and single-cell analyses characterize patient-derived tumor organoids to enable personalized therapy for head and neck squamous cell carcinoma. Cancer Res. 2025;85:2726-42.

199. Vlachogiannis G, Hedayat S, Vatsiou A, et al. Patient-derived organoids model treatment response of metastatic gastrointestinal cancers. Science. 2018;359:920-6.

200. Yao Y, Xu X, Yang L, et al. Patient-derived organoids predict chemoradiation responses of locally advanced rectal cancer. Cell Stem Cell. 2020;26:17-26.e6.

201. Beutel AK, Schütte L, Scheible J, et al. A prospective feasibility trial to challenge patient-derived pancreatic cancer organoids in predicting treatment response. Cancers. 2021;13:2539.

202. Zhang Y, Hu Q, Pei Y, et al. A patient-specific lung cancer assembloid model with heterogeneous tumor microenvironments. Nat Commun. 2024;15:3382.

203. Ooft SN, Weeber F, Schipper L, et al. Prospective experimental treatment of colorectal cancer patients based on organoid drug responses. ESMO Open. 2021;6:100103.

204. Schaffrin-Nabe D, Josten-Nabe A, Schuster S, et al. Real-world applications of comprehensive tumor profiling for personalized cancer therapy in metastatic patients. J Oncol Res Ther. 2025. Available from: https://www.datarpgx.de/wp-content/uploads/2025/08/JONT-10289-1.2.pdf. [Last accessed on 8 May 2026].

205. Yoon S, Kilicarslan You D, Jeong U, et al. Microfluidics in high-throughput drug screening: organ-on-a-chip and C. elegans-based innovations. Biosensors. 2024;14:55.

206. Papamichail L, Koch LS, Veerman D, Broersen K, van der Meer AD. Organoids-on-a-chip: microfluidic technology enables culture of organoids with enhanced tissue function and potential for disease modeling. Front Bioeng Biotechnol. 2025;13:1515340.

207. Chauhdari T, Zaidi SA, Su J, Ding Y. Organoids meet microfluidics: recent advancements, challenges, and future of organoids-on-chip. In Vitro Model. 2025;4:71-88.

208. Rouvinov K, Naamneh R, Yakobson A, et al. The transformative potential of liquid biopsies and circulating tumor DNA (ctDNA) in modern oncology. Diagnostics. 2026;16:523.

209. Mohd Zuhdi NF, Siddig A, Mohd Nafi SN, et al. Next-generation sequencing in breast cancer: current clinical applications and future directions. Ann Med. 2025;57:2569989.

210. Mirza M, Goerke L, Anderson A, Wilsdon T. Assessing the cost-effectiveness of next-generation sequencing as a biomarker testing approach in oncology and policy implications: a literature review. Value Health. 2024;27:1300-9.

211. Hong TH, Cha H, Shim JH, et al. Clinical advantage of targeted sequencing for unbiased tumor mutational burden estimation in samples with low tumor purity. J Immunother Cancer. 2020;8:e001199.

212. Allam M, Cai S, Coskun AF. Multiplex bioimaging of single-cell spatial profiles for precision cancer diagnostics and therapeutics. NPJ Precis Oncol. 2020;4:11.

213. Wharton KA Jr, Wood D, Manesse M, Maclean KH, Leiss F, Zuraw A. Tissue multiplex analyte detection in anatomic pathology - pathways to clinical implementation. Front Mol Biosci. 2021;8:672531.

214. Ghazali N, Ortega-Franco A, de Miguel-Perez D, et al. Cancer in a drop: Liquid biopsy highlights from the World Conference on Lung Cancer (WCLC) 2025. J Liq Biopsy. 2025;10:100449.

215. Abbosh C, Frankell AM, Harrison T, et al.; TRACERx Consortium. Tracking early lung cancer metastatic dissemination in TRACERx using ctDNA. Nature. 2023;616:553-62.

Cancer Drug Resistance
ISSN 2578-532X (Online)

Portico

All published articles will preserved here permanently:

https://www.portico.org/publishers/oae/

Portico

All published articles will preserved here permanently:

https://www.portico.org/publishers/oae/