{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:23:38Z","timestamp":1785425018359,"version":"3.56.0"},"reference-count":94,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T00:00:00Z","timestamp":1784246400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100010814","name":"Natural Science Research Project of Anhui Educational Committee","doi-asserted-by":"publisher","award":["2023AH051201"],"award-info":[{"award-number":["2023AH051201"]}],"id":[{"id":"10.13039\/501100010814","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010814","name":"Natural Science Research Project of Anhui Educational Committee","doi-asserted-by":"publisher","award":["2023AH051200"],"award-info":[{"award-number":["2023AH051200"]}],"id":[{"id":"10.13039\/501100010814","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62502005"],"award-info":[{"award-number":["62502005"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["62501014"],"award-info":[{"award-number":["62501014"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["62502005"],"award-info":[{"award-number":["62502005"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["62501014"],"award-info":[{"award-number":["62501014"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: The cellular heterogeneity and spatial organization patterns of the tumor microenvironment (TME) play a crucial role in colorectal cancer (CRC) progression, but their spatial distribution and cellular communication mechanisms require further elucidation. This study aims to systematically dissect the cellular heterogeneity and spatial organization characteristics of the CRC microenvironment by integrating single-cell and spatial transcriptomic data. Methods: Single-cell RNA sequencing and spatial transcriptomics data of primary CRC were integrated to characterize the TME. Intercellular signaling patterns were elucidated through communication analysis, spatial niche clustering, ligand\u2013receptor pair analysis, and spatial expression mapping. The ESTIMATE algorithm was applied to assess the correlation between TME scores and pathway-associated genes. Drug sensitivity prediction was performed using the oncoPredict. Results: Single-cell analysis identifies nine major cell types, revealing significant cellular heterogeneity. Intercellular communication analysis demonstrates that the MIF signaling pathway plays a prominent role within the TME communication network, with MIF-(CD74+CD44) and MIF-(CD74+CXCR4) identified as dominant receptor complexes. Spatial transcriptomic analysis reveals distinct spatial functional partitioning of these signaling axes. Signaling flow analysis indicates an immunosuppressive \u201ctumor\u2013immune\u201d axis mediated by MIF signaling from tumor epithelial cells to immune cells. MIF expression is negatively correlated with ImmuneScore, while its receptors CD74, CD44, and CXCR4 are positively correlated. Drug sensitivity analysis reveals potential associations between key genes (MIF, CD74, CD44, and CXCR4) in the MIF pathway and various anti-tumor drugs. Conclusions: Our study reveals the cellular heterogeneity of the CRC microenvironment from multiple perspectives, elucidates the key mechanisms of the MIF signaling pathway, and provides potential therapeutic targets for CRC treatment.<\/jats:p>","DOI":"10.3390\/genes17070817","type":"journal-article","created":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T12:00:17Z","timestamp":1784548817000},"page":"817","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrated Single-Cell and Spatial Transcriptomic Analysis Reveals the Immunoregulatory Role of MIF Signaling in Colorectal Cancer"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1458-9648","authenticated-orcid":false,"given":"Yuxian","family":"Liu","sequence":"first","affiliation":[{"name":"School of Artificial Intelligence, Anhui University of Science & Technology, Huainan 232001, China"},{"name":"State Key Laboratory of Digital Intelligent Technology for Unmanned Coal Mining, Anhui University of Science & Technology, Huainan 232001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyuan","family":"Zhang","sequence":"additional","affiliation":[{"name":"School of Artificial Intelligence, Anhui University of Science & Technology, Huainan 232001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Li","sequence":"additional","affiliation":[{"name":"School of Artificial Intelligence, Anhui University of Science & Technology, Huainan 232001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingjie","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Artificial Intelligence, Anhui University of Science & Technology, Huainan 232001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangcheng","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Artificial Intelligence, Anhui University of Science & Technology, Huainan 232001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1508-4131","authenticated-orcid":false,"given":"Yanni","family":"Cao","sequence":"additional","affiliation":[{"name":"School of Artificial Intelligence, Anhui University of Science & Technology, Huainan 232001, China"},{"name":"State Key Laboratory of Digital Intelligent Technology for Unmanned Coal Mining, Anhui University of Science & Technology, Huainan 232001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,17]]},"reference":[{"key":"ref_1","first-page":"e70043","article-title":"Cancer statistics, 2026","volume":"76","author":"Siegel","year":"2026","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1146\/annurev-biodatasci-020722-091857","article-title":"Single-Cell RNA Sequencing for Studying Human Cancers","volume":"6","author":"Aran","year":"2023","journal-title":"Annu Rev. BioMed Data Sci."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.15252\/embr.201439246","article-title":"The extracellular matrix modulates the hallmarks of cancer","volume":"15","author":"Pickup","year":"2014","journal-title":"EMBO Rep."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1126\/science.aaa6204","article-title":"T cell exclusion, immune privilege, and the tumor microenvironment","volume":"348","author":"Joyce","year":"2015","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1458","DOI":"10.1038\/s41587-019-0332-7","article-title":"Single-cell multiomic analysis identifies regulatory programs in mixed-phenotype acute leukemia","volume":"37","author":"Granja","year":"2019","journal-title":"Nat. Biotechnol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1038\/nri.2017.76","article-title":"Single-cell RNA sequencing to explore immune cell heterogeneity","volume":"18","author":"Papalexi","year":"2018","journal-title":"Nat. Rev. Immunol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"dev170506","DOI":"10.1242\/dev.170506","article-title":"Concepts and limitations for learning developmental trajectories from single cell genomics","volume":"146","author":"Tritschler","year":"2019","journal-title":"Development"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/s41588-020-0636-z","article-title":"Lineage-dependent gene expression programs influence the immune landscape of colorectal cancer","volume":"52","author":"Lee","year":"2020","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1016\/j.cell.2020.03.048","article-title":"Single-Cell Analyses Inform Mechanisms of Myeloid-Targeted Therapies in Colon Cancer","volume":"181","author":"Zhang","year":"2020","journal-title":"Cell."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1637144","DOI":"10.3389\/fimmu.2025.1637144","article-title":"Single-cell technology reveals the crosstalk between tumor cells and immune cells: Driving immune signal transduction and inflammation-mediated cardiac dysfunction in the tumor microenvironment of colorectal cancer","volume":"16","author":"Nie","year":"2025","journal-title":"Front Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1038\/s41588-021-00911-1","article-title":"A single-cell and spatially resolved atlas of human breast cancers","volume":"53","author":"Wu","year":"2021","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e2205395","DOI":"10.1002\/advs.202205395","article-title":"Combined Single-Cell and Spatial Transcriptomics Reveal the Metabolic Evolvement of Breast Cancer during Early Dissemination","volume":"10","author":"Liu","year":"2023","journal-title":"Adv. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e2412146122","DOI":"10.1073\/pnas.2412146122","article-title":"Spatial Patterning Analysis of Cellular Ensembles (SPACE) finds complex spatial organization at the cell and tissue levels","volume":"122","author":"Schrom","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s12943-024-02040-9","article-title":"Advances in spatial transcriptomics and its applications in cancer research","volume":"23","author":"Jin","year":"2024","journal-title":"Mol. Cancer"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1186\/s12967-024-05307-3","article-title":"Progress of single-cell RNA sequencing combined with spatial transcriptomics in tumour microenvironment and treatment of pancreatic cancer","volume":"22","author":"Zhu","year":"2024","journal-title":"J. Transl. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1097\/HEP.0000000000000387","article-title":"Single-cell and spatially resolved transcriptomics for liver biology","volume":"80","author":"Lin","year":"2024","journal-title":"Hepatology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"5970","DOI":"10.1158\/0008-5472.CAN-18-0747","article-title":"Spatially Resolved Transcriptomics Enables Dissection of Genetic Heterogeneity in Stage III Cutaneous Malignant Melanoma","volume":"78","author":"Thrane","year":"2018","journal-title":"Cancer Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2419","DOI":"10.1038\/s41467-018-04724-5","article-title":"Spatial maps of prostate cancer transcriptomes reveal an unexplored landscape of heterogeneity","volume":"9","author":"Berglund","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"111929","DOI":"10.1016\/j.celrep.2022.111929","article-title":"Spatial and single-cell transcriptomics decipher the cellular environment containing HLA-G+ cancer cells and SPP1+ macrophages in colorectal cancer","volume":"42","author":"Ozato","year":"2023","journal-title":"Cell Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1038\/s41580-024-00768-2","article-title":"Profiling cell identity and tissue architecture with single-cell and spatial transcriptomics","volume":"26","author":"Gulati","year":"2025","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"906","DOI":"10.1093\/jmcb\/mjaa028","article-title":"Transcriptional output, cell-type densities, and normalization in spatial transcriptomics","volume":"12","author":"Saiselet","year":"2020","journal-title":"J. Mol. Cell Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41587-019-0392-8","article-title":"Integrating microarray-based spatial transcriptomics and single-cell RNA-seq reveals tissue architecture in pancreatic ductal adenocarcinomas","volume":"38","author":"Moncada","year":"2020","journal-title":"Nat. Biotechnol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ahmed, R., Zaman, T., Chowdhury, F., Mraiche, F., Tariq, M., Ahmad, I.S., and Hasan, A. (2022). Single-Cell RNA Sequencing with Spatial Transcriptomics of Cancer Tissues. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23063042"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e005475","DOI":"10.1136\/jitc-2022-005475","article-title":"OxMIF: A druggable isoform of macrophage migration inhibitory factor in cancer and inflammatory diseases","volume":"10","author":"Thiele","year":"2022","journal-title":"J. Immunother. Cancer"},{"key":"ref_25","first-page":"149","article-title":"Macrophage migration inhibitory factor: Exploring physiological roles and comparing health benefits against oncogenic and autoimmune risks (Review)","volume":"56","year":"2025","journal-title":"Int. J. Mol. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2652","DOI":"10.1158\/2159-8290.CD-22-1467","article-title":"Oncogenic KRAS Drives Lipofibrogenesis to Promote Angiogenesis and Colon Cancer Progression","volume":"13","author":"Hsu","year":"2023","journal-title":"Cancer Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"eadf5464","DOI":"10.1126\/sciadv.adf5464","article-title":"Single-cell and spatial transcriptome analysis reveals the cellular heterogeneity of liver metastatic colorectal cancer","volume":"9","author":"Wang","year":"2023","journal-title":"Sci. Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e36","DOI":"10.1002\/imt2.36","article-title":"Sangerbox: A comprehensive, interaction-friendly clinical bioinformatics analysis platform","volume":"1","author":"Shen","year":"2022","journal-title":"Imeta"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.1038\/s41467-024-48706-2","article-title":"Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer","volume":"15","author":"Langerud","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3573","DOI":"10.1016\/j.cell.2021.04.048","article-title":"Integrated analysis of multimodal single-cell data","volume":"184","author":"Hao","year":"2021","journal-title":"Cell."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, sensitive and accurate integration of single-cell data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"D870","DOI":"10.1093\/nar\/gkac947","article-title":"CellMarker 2.0: An updated database of manually curated cell markers in human\/mouse and web tools based on scRNA-seq data","volume":"51","author":"Hu","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1038\/s41556-021-00787-7","article-title":"Cell type ontologies of the Human Cell Atlas","volume":"23","author":"Xu","year":"2021","journal-title":"Nat. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"H\u00e4nzelmann, S., Castelo, R., and Guinney, J. (2013). GSVA: Gene set variation analysis for microarray and RNA-seq data. BMC Bioinform., 14.","DOI":"10.1186\/1471-2105-14-7"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1038\/s41467-021-21246-9","article-title":"Inference and analysis of cell-cell communication using CellChat","volume":"12","author":"Jin","year":"2021","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"btac775","DOI":"10.1093\/bioinformatics\/btac775","article-title":"Comprehensive visualization of cell-cell interactions in single-cell and spatial transcriptomics with NICHES","volume":"39","author":"Raredon","year":"2023","journal-title":"Bioinformatics"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1038\/s41592-019-0667-5","article-title":"NicheNet: Modeling intercellular communication by linking ligands to target genes","volume":"17","author":"Browaeys","year":"2020","journal-title":"Nat. Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1093\/ije\/dyq191","article-title":"The proof and measurement of association between two things","volume":"39","author":"Spearman","year":"2010","journal-title":"Int. J. Epidemiol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"bbab260","DOI":"10.1093\/bib\/bbab260","article-title":"OncoPredict: An R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data","volume":"22","author":"Maeser","year":"2021","journal-title":"Brief. Bioinform."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e2319055121","DOI":"10.1073\/pnas.2319055121","article-title":"Phenotypic screen of sixty-eight colorectal cancer cell lines identifies CEACAM6 and CEACAM5 as markers of acid resistance","volume":"121","author":"Michl","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/j.celrep.2014.04.036","article-title":"LIF mediates proinvasive activation of stromal fibroblasts in cancer","volume":"7","author":"Albrengues","year":"2014","journal-title":"Cell Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1038\/s41568-019-0238-1","article-title":"A framework for advancing our understanding of cancer-associated fibroblasts","volume":"20","author":"Sahai","year":"2020","journal-title":"Nat. Rev. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1186\/s13046-025-03493-6","article-title":"HAS1(high) cancer associated fibroblasts located at the tumor invasion front zone promote oral squamous cell carcinoma invasion via ECM remodeling","volume":"44","author":"Jin","year":"2025","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_44","first-page":"953","article-title":"Haptoglobin expression in human colorectal cancer","volume":"34","author":"Harding","year":"2019","journal-title":"Histol. Histopathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1186\/s12967-025-06376-8","article-title":"Single-cell RNA sequencing and spatial transcriptomics reveal the heterogeneity and intercellular communication of cancer-associated fibroblasts in gastric cancer","volume":"23","author":"Zhang","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.ccell.2023.12.002","article-title":"EGFR-activated myofibroblasts promote metastasis of pancreatic cancer","volume":"42","author":"Mucciolo","year":"2024","journal-title":"Cancer Cell."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"217452","DOI":"10.1016\/j.canlet.2025.217452","article-title":"Single-cell transcriptomics reveals intratumor heterogeneity and the potential roles of cancer stem cells and myCAFs in colorectal cancer liver metastasis and recurrence","volume":"612","author":"Zhan","year":"2025","journal-title":"Cancer Lett."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1186\/s13287-022-02913-0","article-title":"Characterization of stem cell landscape and identification of stemness-relevant prognostic gene signature to aid immunotherapy in colorectal cancer","volume":"13","author":"Zheng","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1186\/s12943-025-02475-8","article-title":"The controversial role of senescence-associated secretory phenotype (SASP) in cancer therapy","volume":"24","author":"Cao","year":"2025","journal-title":"Mol. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1038\/ni904","article-title":"Foxp3 programs the development and function of CD4+CD25+ regulatory T cells","volume":"4","author":"Fontenot","year":"2003","journal-title":"Nat. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1038\/nature12199","article-title":"BACH2 represses effector programs to stabilize T(reg)-mediated immune homeostasis","volume":"498","author":"Roychoudhuri","year":"2013","journal-title":"Nature"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2202","DOI":"10.1016\/j.immuni.2024.06.014","article-title":"Distinct epigenomic landscapes underlie tissue-specific memory T cell differentiation","volume":"57","author":"Buquicchio","year":"2024","journal-title":"Immunity"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"103324","DOI":"10.1016\/j.jaut.2024.103324","article-title":"Unraveling the immunomodulatory impact of hydroxychloroquine on peripheral T cells using single-cell RNA sequencing","volume":"149","author":"Long","year":"2024","journal-title":"J. Autoimmun."},{"key":"ref_54","first-page":"7758","article-title":"IL4I1 and tryptophan metabolites enhance AHR signals to facilitate colorectal cancer progression and immunosuppression","volume":"14","author":"Sun","year":"2022","journal-title":"Am. J. Transl. Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Fey, R.M., Nichols, R.A., Tran, T.T., Vandenbark, A.A., and Kulkarni, R.P. (2024). MIF and CD74 as Emerging Biomarkers for Immune Checkpoint Blockade Therapy. Cancers, 16.","DOI":"10.3390\/cancers16091773"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"3224","DOI":"10.1038\/s41467-022-30755-0","article-title":"Comparison of methods and resources for cell-cell communication inference from single-cell RNA-Seq data","volume":"13","author":"Dimitrov","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/s41576-020-00292-x","article-title":"Deciphering cell-cell interactions and communication from gene expression","volume":"22","author":"Armingol","year":"2021","journal-title":"Nat. Rev. Genet."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1076","DOI":"10.1038\/s41592-022-01575-3","article-title":"Cell type-specific inference of differential expression in spatial transcriptomics","volume":"19","author":"Cable","year":"2022","journal-title":"Nat. Methods"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1418","DOI":"10.1158\/2159-8290.CD-23-1300","article-title":"Spatially Segregated Macrophage Populations Predict Distinct Outcomes in Colon Cancer","volume":"14","author":"Matusiak","year":"2024","journal-title":"Cancer Discov."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"108024","DOI":"10.1016\/j.pharmthera.2021.108024","article-title":"Macrophage migration inhibitory factor (MIF): A multifaceted cytokine regulated by genetic and physiological strategies","volume":"233","author":"Sumaiya","year":"2022","journal-title":"Pharmacol. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"107447","DOI":"10.1016\/j.pharmthera.2019.107447","article-title":"5-fluorouracil and other fluoropyrimidines in colorectal cancer: Past, present and future","volume":"206","author":"Vodenkova","year":"2020","journal-title":"Pharmacol. Ther."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s10565-024-09982-2","article-title":"ANXA10 sensitizes microsatellite instability-high colorectal cancer to anti-PD-1 immunotherapy via assembly of HLA-DR dimers by regulating CD74","volume":"41","author":"Sun","year":"2025","journal-title":"Cell Biol. Toxicol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"105299","DOI":"10.18632\/oncotarget.22169","article-title":"Immunological landscape of consensus clusters in colorectal cancer","volume":"8","author":"Karpinski","year":"2017","journal-title":"Oncotarget"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1120","DOI":"10.1038\/nbt.2038","article-title":"Single-cell dissection of transcriptional heterogeneity in human colon tumors","volume":"29","author":"Dalerba","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1184167","DOI":"10.3389\/fimmu.2023.1184167","article-title":"Integration of single-cell RNA sequencing and bulk RNA transcriptome sequencing reveals a heterogeneous immune landscape and pivotal cell subpopulations associated with colorectal cancer prognosis","volume":"14","author":"Zhang","year":"2023","journal-title":"Front Immunol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"e70012","DOI":"10.1002\/biof.70012","article-title":"Spatial and single-cell transcriptomic analysis reveals fibroblasts dependent immune environment in colorectal cancer","volume":"51","author":"Jia","year":"2025","journal-title":"Biofactors"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"1375543","DOI":"10.3389\/fcell.2024.1375543","article-title":"The role of cancer-associated fibroblasts in the invasion and metastasis of colorectal cancer","volume":"12","author":"Yin","year":"2024","journal-title":"Front Cell Dev. Biol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/s12943-019-1019-x","article-title":"CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer","volume":"18","author":"Hu","year":"2019","journal-title":"Mol. Cancer"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1378302","DOI":"10.3389\/fcell.2024.1378302","article-title":"The hidden messengers: Cancer associated fibroblasts-derived exosomal miRNAs as key regulators of cancer malignancy","volume":"12","author":"Gou","year":"2024","journal-title":"Front Cell Dev. Biol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1480","DOI":"10.1016\/j.ccell.2024.08.011","article-title":"Classifying cancer-associated fibroblasts-The good, the bad, and the target","volume":"42","author":"Cords","year":"2024","journal-title":"Cancer Cell."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1362140","DOI":"10.3389\/fimmu.2024.1362140","article-title":"Precursor exhausted CD8(+)T cells in colorectal cancer tissues associated with patient\u2019s survival and immunotherapy responsiveness","volume":"15","author":"Huang","year":"2024","journal-title":"Front Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.canlet.2019.10.016","article-title":"Single-cell transcriptome analysis reveals tumor immune microenvironment heterogenicity and granulocytes enrichment in colorectal cancer liver metastases","volume":"470","author":"Zhang","year":"2020","journal-title":"Cancer Lett."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"e70041","DOI":"10.1002\/cam4.70041","article-title":"Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges","volume":"13","author":"Dang","year":"2024","journal-title":"Cancer Med."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1532971","DOI":"10.3389\/fphar.2025.1532971","article-title":"Precision medicine in colorectal cancer: Genomics profiling and targeted treatment","volume":"16","author":"Velaro","year":"2025","journal-title":"Front Pharmacol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1093\/qjmed\/hcq148","article-title":"Inflammation and cancer: Macrophage migration inhibitory factor (MIF)--the potential missing link","volume":"103","author":"Conroy","year":"2010","journal-title":"Qjm"},{"key":"ref_76","first-page":"561","article-title":"[Research progress in macrophage migration inhibitory factor (MIF) in tumor immune response]","volume":"40","author":"Xie","year":"2024","journal-title":"Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi"},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1159\/000496027","article-title":"Concurrent Expression of CD47 and CD44 in Colorectal Cancer Promotes Malignancy","volume":"86","author":"Sasaki","year":"2019","journal-title":"Pathobiology"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e009024-17","DOI":"10.1136\/jitc-2024-009024","article-title":"Targeting tumor-associated macrophage-derived CD74 improves efficacy of neoadjuvant chemotherapy in combination with PD-1 blockade for cervical cancer","volume":"12","author":"Wang","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1431535","DOI":"10.3389\/fimmu.2024.1431535","article-title":"Gastrointestinal stromal tumors regulate macrophage M2 polarization through the MIF\/CXCR4 axis to immune escape","volume":"15","author":"Xiao","year":"2024","journal-title":"Front Immunol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1016\/j.cellsig.2019.01.006","article-title":"Evolving complexity of MIF signaling","volume":"57","author":"Jankauskas","year":"2019","journal-title":"Cell Signal."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1186\/s12967-022-03395-7","article-title":"Single-cell N(6)-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy","volume":"20","author":"Gao","year":"2022","journal-title":"J. Transl. Med."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12964-024-02020-y","article-title":"Integrative analysis of Ewing\u2019s sarcoma reveals that the MIF-CD74 axis is a target for immunotherapy","volume":"23","author":"He","year":"2025","journal-title":"Cell Commun. Signal."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.3389\/fimmu.2018.01132","article-title":"Blockade of MIF-CD74 Signalling on Macrophages and Dendritic Cells Restores the Antitumour Immune Response Against Metastatic Melanoma","volume":"9","author":"Figueiredo","year":"2018","journal-title":"Front Immunol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s13046-016-0475-z","article-title":"MIF\/CD74 axis is a target for novel therapies in colon carcinomatosis","volume":"36","author":"Bozzi","year":"2017","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"217181","DOI":"10.1016\/j.canlet.2024.217181","article-title":"Spatial transcriptomic revealed intratumor heterogeneity and cancer stem cell enrichment in colorectal cancer metastasis","volume":"602","author":"Zhou","year":"2024","journal-title":"Cancer Lett."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1038\/s41419-021-03426-z","article-title":"Hsp90-stabilized MIF supports tumor progression via macrophage recruitment and angiogenesis in colorectal cancer","volume":"12","author":"Klemke","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1186\/s40246-025-00805-x","article-title":"Spatial transcriptomics and scRNA-seq: Decoding tumor complexity and constructing prognostic models in colorectal cancer","volume":"19","author":"Song","year":"2025","journal-title":"Hum. Genom."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41576-023-00685-8","article-title":"The diversification of methods for studying cell-cell interactions and communication","volume":"25","author":"Armingol","year":"2024","journal-title":"Nat. Rev. Genet."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.coisb.2021.03.007","article-title":"The landscape of cell-cell communication through single-cell transcriptomics","volume":"26","author":"Almet","year":"2021","journal-title":"Curr. Opin. Syst. Biol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"121476","DOI":"10.1016\/j.lfs.2023.121476","article-title":"CopA3 peptide inhibits MDM2-p53 complex stability in colorectal cancers and activates p53 mediated cell death machinery","volume":"318","author":"Dey","year":"2023","journal-title":"Life Sci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"2978","DOI":"10.1200\/JCO.23.01889","article-title":"Neoadjuvant Chemotherapy With Oxaliplatin and Fluoropyrimidine Versus Upfront Surgery for Locally Advanced Colon Cancer: The Randomized, Phase III OPTICAL Trial","volume":"42","author":"Hu","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"112198","DOI":"10.1016\/j.intimp.2024.112198","article-title":"The Macrophage migration inhibitory factor is a vital player in Pan-Cancer by functioning as a M0 Macrophage biomarker","volume":"134","author":"Pu","year":"2024","journal-title":"Int. Immunopharmacol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1186\/s12967-023-04150-2","article-title":"Advances in spatial transcriptomics and related data analysis strategies","volume":"21","author":"Du","year":"2023","journal-title":"J. Transl. Med."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"aaa6090","DOI":"10.1126\/science.aaa6090","article-title":"RNA imaging. Spatially resolved, highly multiplexed RNA profiling in single cells","volume":"348","author":"Chen","year":"2015","journal-title":"Science"}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/817\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T16:21:30Z","timestamp":1784650890000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/7\/817"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,17]]},"references-count":94,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["genes17070817"],"URL":"https:\/\/doi.org\/10.3390\/genes17070817","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,17]]}}}