{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,14]],"date-time":"2026-05-14T10:09:46Z","timestamp":1778753386602,"version":"3.51.4"},"reference-count":95,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T00:00:00Z","timestamp":1576195200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Current evidence strongly suggests that cancer cells depend on the microenvironment in order to thrive. In fact, signals from the surrounding tumor microenvironment are crucial for cancer cells\u00b4 aggressiveness, altering their expression profile and favoring their metastatic potential. As such, targeting the tumor microenvironment to impair cancer progression became an attractive therapeutic option. Interestingly, it has been shown that oncogenic KRAS signaling promotes a pro-tumorigenic microenvironment, and the associated crosstalk alters the expression profile of cancer cells. These findings award KRAS a key role in controlling the interactions between cancer cells and the microenvironment, granting cancer a poor prognosis. Given the lack of effective approaches to target KRAS itself or its downstream effectors in the clinic, exploring such interactions may open new perspectives on possible therapeutic strategies to hinder mutant KRAS tumors. This review highlights those communications and their implications for the development of effective therapies or to provide insights regarding response to existing regimens.<\/jats:p>","DOI":"10.3390\/cancers11122010","type":"journal-article","created":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T11:27:22Z","timestamp":1576236442000},"page":"2010","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Targeting the Tumor Microenvironment: An Unexplored Strategy for Mutant KRAS Tumors"],"prefix":"10.3390","volume":"11","author":[{"given":"Patr\u00edcia","family":"Dias Carvalho","sequence":"first","affiliation":[{"name":"i3S \u2013 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Epithelial Interactions in Cancer group, Rua Alfredo Allen, 4200-135 Porto, Portugal"},{"name":"IPATIMUP \u2013 Institute of Molecular Pathology and Immunology of the University of Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"ICBAS - Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, R. Jorge de Viterbo Ferreira 228, 4050-313 Porto, Portugal"}]},{"given":"Ana Lu\u00edsa","family":"Machado","sequence":"additional","affiliation":[{"name":"i3S \u2013 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Epithelial Interactions in Cancer group, Rua Alfredo Allen, 4200-135 Porto, Portugal"},{"name":"INEB \u2013 Institute of Biomedical Engineering, Tumor and Microenvironment group, Rua Alfredo Allen, 4200-135 Porto, Portugal"},{"name":"Ci\u00eancias Qu\u00edmicas e das Biomol\u00e9culas, Centro de Investiga\u00e7\u00e3o em Sa\u00fade e Ambiente, Escola Superior de Sa\u00fade do Porto, Instituto Polit\u00e9cnico do Porto, 4200-072, Porto, Portugal"}]},{"given":"Fl\u00e1via","family":"Martins","sequence":"additional","affiliation":[{"name":"i3S \u2013 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Epithelial Interactions in Cancer group, Rua Alfredo Allen, 4200-135 Porto, Portugal"},{"name":"IPATIMUP \u2013 Institute of Molecular Pathology and Immunology of the University of Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, FMUP \u2013 Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal"}]},{"given":"Raquel","family":"Seruca","sequence":"additional","affiliation":[{"name":"i3S \u2013 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Epithelial Interactions in Cancer group, Rua Alfredo Allen, 4200-135 Porto, Portugal"},{"name":"IPATIMUP \u2013 Institute of Molecular Pathology and Immunology of the University of Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"},{"name":"Department of Pathology, FMUP \u2013 Faculty of Medicine of the University of Porto, 4200-319 Porto, Portugal"}]},{"given":"S\u00e9rgia","family":"Velho","sequence":"additional","affiliation":[{"name":"i3S \u2013 Instituto de Investiga\u00e7\u00e3o e Inova\u00e7\u00e3o em Sa\u00fade, Epithelial Interactions in Cancer group, Rua Alfredo Allen, 4200-135 Porto, Portugal"},{"name":"IPATIMUP \u2013 Institute of Molecular Pathology and Immunology of the University of Porto, Rua J\u00falio Amaral de Carvalho 45, 4200-135 Porto, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2019,12,13]]},"reference":[{"key":"ref_1","first-page":"4682","article-title":"Ras Oncogenes in Human Cancer: A Review","volume":"49","author":"Bos","year":"1989","journal-title":"Cancer Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1016\/j.trecan.2017.08.006","article-title":"KRAS Alleles: The Devil Is in the Detail","volume":"3","author":"Haigis","year":"2017","journal-title":"Trends Cancer"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1242\/jcs.182873","article-title":"RAS isoforms and mutations in cancer at a glance","volume":"129","author":"Hobbs","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"12153","DOI":"10.3390\/ijms131012153","article-title":"Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer","volume":"13","author":"Arrington","year":"2012","journal-title":"Int. J. Mol. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.lungcan.2015.11.004","article-title":"Correlation between KRAS mutation status and response to chemotherapy in patients with advanced non-small cell lung cancer","volume":"92","author":"Hames","year":"2016","journal-title":"Lung Cancer"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"146","DOI":"10.1186\/s12957-016-0888-3","article-title":"Prognostic significance of K-ras mutations in pancreatic cancer: A meta-analysis","volume":"14","author":"Tao","year":"2016","journal-title":"World J. Surg. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/annonc\/mdq680","article-title":"Different types of K-Ras mutations could affect drug sensitivity and tumour behaviour in non-small-cell lung cancer","volume":"22","author":"Garassino","year":"2011","journal-title":"Ann. Oncol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.1245\/s10434-013-2910-0","article-title":"Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma","volume":"20","author":"Duldulao","year":"2013","journal-title":"Ann. Surg. Oncol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"714","DOI":"10.1002\/cncr.27804","article-title":"KRAS p.G13D mutation and codon 12 mutations are not created equal in predicting clinical outcomes of cetuximab in metastatic colorectal cancer: A systematic review and meta-analysis","volume":"119","author":"Mao","year":"2013","journal-title":"Cancer"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nrd4389","article-title":"Drugging the undruggable RAS: Mission Possible?","volume":"13","author":"Cox","year":"2014","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1158","DOI":"10.1126\/science.aam7622","article-title":"Drugging RAS: Know the enemy","volume":"355","author":"Papke","year":"2017","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1158\/2159-8290.CD-13-0128","article-title":"Two is better than one: Combining IGF1R and MEK blockade as a promising novel treatment strategy against KRAS-mutant lung cancer","volume":"3","author":"Chen","year":"2013","journal-title":"Cancer Discov."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"eaao2565","DOI":"10.1126\/scitranslmed.aao2565","article-title":"The ERBB network facilitates KRAS-driven lung tumorigenesis","volume":"10","author":"Kruspig","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"eaao2301","DOI":"10.1126\/scitranslmed.aao2301","article-title":"Afatinib restrains K-RAS-driven lung tumorigenesis","volume":"10","author":"Moll","year":"2018","journal-title":"Sci. Transl. Med."},{"key":"ref_15","unstructured":"Hallin, J., Engstrom, L.D., Hargis, L., Calinisan, A., Aranda, R., Briere, D.M., Sudhakar, N., Bowcut, V., Baer, B.R., and Ballard, J.A. (2019). The KRASG12C Inhibitor, MRTX849, Provides Insight Toward Therapeutic Susceptibility of KRAS Mutant Cancers in Mouse Models and Patients. Cancer Discov., CD-19-1167."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1038\/nature12138","article-title":"Macropinocytosis of protein is an amino acid supply route in Ras-transformed cells","volume":"497","author":"Commisso","year":"2013","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1038\/s41591-019-0367-9","article-title":"Protective autophagy elicited by RAF\u2192MEK\u2192ERK inhibition suggests a treatment strategy for RAS-driven cancers","volume":"25","author":"Kinsey","year":"2019","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"848","DOI":"10.3389\/fonc.2019.00848","article-title":"KRAS-Driven Metabolic Rewiring Reveals Novel Actionable Targets in Cancer","volume":"9","author":"Pupo","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4945","DOI":"10.1038\/s41467-018-07472-8","article-title":"Oncogenic KRAS supports pancreatic cancer through regulation of nucleotide synthesis","volume":"9","author":"Roeth","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1038\/nrm2438","article-title":"Ras oncogenes: Split personalities","volume":"9","author":"Karnoub","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11360","DOI":"10.1038\/ncomms11360","article-title":"Identification of pyrazolopyridazinones as PDEdelta inhibitors","volume":"7","author":"Papke","year":"2016","journal-title":"Nat. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1038\/nature12205","article-title":"Small molecule inhibition of the KRAS-PDEdelta interaction impairs oncogenic KRAS signalling","volume":"497","author":"Zimmermann","year":"2013","journal-title":"Nature"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"410","DOI":"10.1038\/s41586-019-1062-1","article-title":"Syndecan 1 is a critical mediator of macropinocytosis in pancreatic cancer","volume":"568","author":"Yao","year":"2019","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.jconrel.2019.01.014","article-title":"KRAS-enhanced macropinocytosis and reduced FcRn-mediated recycling sensitize pancreatic cancer to albumin-conjugated drugs","volume":"296","author":"Liu","year":"2019","journal-title":"J. Control. Release"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"656","DOI":"10.1016\/j.cell.2012.01.058","article-title":"Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism","volume":"149","author":"Ying","year":"2012","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ccr.2012.11.007","article-title":"Synthetic Lethal Interaction of Combined BCL-XL and MEK Inhibition Promotes Tumor Regressions in KRAS Mutant Cancer Models","volume":"23","author":"Corcoran","year":"2013","journal-title":"Cancer Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1016\/j.cell.2011.12.033","article-title":"TAK1 inhibition promotes apoptosis in KRAS-dependent colon cancers","volume":"148","author":"Singh","year":"2012","journal-title":"Cell"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"a031518","DOI":"10.1101\/cshperspect.a031518","article-title":"Synthetic lethal vulnerabilities in kras-mutant cancers","volume":"8","author":"Aguirre","year":"2018","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1802","DOI":"10.1158\/1078-0432.CCR-14-2180","article-title":"RAS synthetic lethal screens revisited: Still seeking the elusive prize?","volume":"21","author":"Downward","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.ccr.2012.02.022","article-title":"Accessories to the Crime: Functions of Cells Recruited to the Tumor Microenvironment","volume":"21","author":"Hanahan","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1423","DOI":"10.1038\/nm.3394","article-title":"Microenvironmental regulation of tumor progression and metastasis","volume":"19","author":"Quail","year":"2013","journal-title":"Nat. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"a026781","DOI":"10.1101\/cshperspect.a026781","article-title":"Tumor microenvironment and differential responses to therapy","volume":"7","author":"Hirata","year":"2017","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3468","DOI":"10.2741\/2327","article-title":"Targeting the tumor microenvironment","volume":"12","author":"Kenny","year":"2007","journal-title":"Front. Biosci."},{"key":"ref_34","first-page":"85","article-title":"Targeting the tumor microenvironment for cancer therapy","volume":"20","author":"Mendes","year":"2019","journal-title":"Int. J. Mol. Sci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1158\/0008-5472.CAN-17-2084","article-title":"KRAS oncogenic signaling extends beyond cancer cells to orchestrate the microenvironment","volume":"78","author":"Carvalho","year":"2018","journal-title":"Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12885-018-5020-3","article-title":"The 2018 Nobel Prize in medicine goes to cancer immunotherapy (editorial for BMC cancer)","volume":"18","author":"Guo","year":"2018","journal-title":"BMC Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Marhelava, K., Pilch, Z., Bajor, M., Graczyk-Jarzynka, A., and Zagozdzon, R. (2019). Targeting negative and positive immune checkpoints with monoclonal antibodies in therapy of cancer. Cancers, 11.","DOI":"10.3390\/cancers11111756"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/s41575-019-0126-x","article-title":"Immunotherapy in colorectal cancer: Rationale, challenges and potential","volume":"16","author":"Ganesh","year":"2019","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_39","first-page":"239","article-title":"Where We Stand With Immunotherapy in Colorectal Cancer: Toxicity Management","volume":"38","author":"Overman","year":"2018","journal-title":"ASCO Educ. B"},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Corrales, L., Scilla, K., Caglevic, C., Miller, K., Oliveira, J., and Rolfo, C. (2018). Immunotherapy in Lung Cancer: A New Age in Cancer Treatment, Springer.","DOI":"10.1007\/978-3-030-02505-2_3"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1002\/ags3.12176","article-title":"Immunotherapy for pancreatic cancer: Barriers and breakthroughs","volume":"2","author":"Torphy","year":"2018","journal-title":"Ann. Gastroenterol. Surg."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/s41586-019-1694-1","article-title":"The clinical KRAS(G12C) inhibitor AMG 510 drives anti-tumour immunity","volume":"575","author":"Canon","year":"2019","journal-title":"Nature"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Sumimoto, H., Takano, A., Teramoto, K., and Daigo, Y. (2016). RAS-mitogen-activated protein kinase signal is required for enhanced PD-L1 expression in human lung cancers. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0166626"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1007\/s00262-017-2005-z","article-title":"KRAS mutation-induced upregulation of PD-L1 mediates immune escape in human lung adenocarcinoma","volume":"66","author":"Chen","year":"2017","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3012","DOI":"10.1158\/1078-0432.CCR-16-2554","article-title":"Potential predictive value of TP53 and KRAS mutation status for response to PD-1 blockade immunotherapy in lung adenocarcinoma","volume":"23","author":"Dong","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1372","DOI":"10.1016\/j.ejso.2017.02.008","article-title":"Association between PD-L1 expression and driven gene status in NSCLC: A meta-analysis","volume":"43","author":"Li","year":"2017","journal-title":"Eur. J. Surg. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/j.lungcan.2018.05.009","article-title":"Effect of mutant variants of the KRAS gene on PD-L1 expression and on the immune microenvironment and association with clinical outcome in lung adenocarcinoma patients","volume":"121","author":"Falk","year":"2018","journal-title":"Lung Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1016\/j.immuni.2017.11.016","article-title":"Oncogenic RAS Signaling Promotes Tumor Immunoresistance by Stabilizing PD-L1 mRNA","volume":"47","author":"Coelho","year":"2017","journal-title":"Immunity"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1158\/1078-0432.CCR-14-2339","article-title":"The BRAF and MEK inhibitors dabrafenib and trametinib: Effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA","volume":"21","author":"Liu","year":"2015","journal-title":"Clin. Cancer Res."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"6253","DOI":"10.1158\/0008-5472.CAN-16-1308","article-title":"Trametinib drives t cell-dependent control of k- ras-mutated tumors by inhibiting pathological myelopoiesis","volume":"76","author":"Allegrezza","year":"2016","journal-title":"Cancer Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1016\/j.immuni.2016.01.024","article-title":"MAP Kinase Inhibition Promotes T Cell and Anti-tumor Activity in Combination with PD-L1 Checkpoint Blockade","volume":"44","author":"Ebert","year":"2016","journal-title":"Immunity"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1186\/s40425-017-0268-8","article-title":"The MEK inhibitor selumetinib complements CTLA-4 blockade by reprogramming the tumor immune microenvironment","volume":"5","author":"Poon","year":"2017","journal-title":"J. Immunother. Cancer"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2105","DOI":"10.1038\/sj.onc.1209237","article-title":"K-ras activation generates an inflammatory response in lung tumors","volume":"25","author":"Ji","year":"2006","journal-title":"Oncogene"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1158\/2159-8290.CD-14-1236","article-title":"Co-occurring genomic alterations define major subsets of KRAS\u2014mutant lung adenocarcinoma with distinct biology, immune profiles, and therapeutic vulnerabilities","volume":"5","author":"Skoulidis","year":"2015","journal-title":"Cancer Discov."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1158\/2159-8290.CD-18-0099","article-title":"STK11\/LKB1 Mutations and PD-1 Inhibitor Resistance in KRAS- Mutant Lung Adenocarcinoma","volume":"8","author":"Skoulidis","year":"2018","journal-title":"Cancer Discov."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1158\/2159-8290.CD-18-0689","article-title":"Suppression of STING associated with lkb1 loss in KRAS-driven lung cancer","volume":"9","author":"Kitajima","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1158\/0008-5472.CAN-15-1439","article-title":"STK11\/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment","volume":"76","author":"Koyama","year":"2016","journal-title":"Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1002\/ijc.26164","article-title":"Oncogenic KRAS-induced interleukin-8 overexpression promotes cell growth and migration and contributes to aggressive phenotypes of non-small cell lung cancer","volume":"130","author":"Sunaga","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4034","DOI":"10.1038\/onc.2012.402","article-title":"Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer","volume":"32","author":"Sunaga","year":"2013","journal-title":"Oncogene"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"5664","DOI":"10.1073\/pnas.1319051111","article-title":"T helper 17 cells play a critical pathogenic role in lung cancer","volume":"111","author":"Chang","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"3189","DOI":"10.1158\/0008-5472.CAN-15-2840","article-title":"IL-6 blockade reprograms the lung tumor microenvironment to limit the development and progression of K-ras mutant lung cancer Mauricio","volume":"76","author":"Caetano","year":"2016","journal-title":"Cancer Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1158\/2326-6066.CIR-17-0655","article-title":"IL22 Promotes Kras Mutant Lung Cancer by Induction of a Pro-Tumor Immune Response and Protection of Stemness Properties","volume":"6","author":"Khosravi","year":"2019","journal-title":"Cancer Immunol. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-46759-8","article-title":"IL-17C-mediated innate inflammation decreases the response to PD-1 blockade in a model of Kras-driven lung cancer","volume":"9","author":"Ritzmann","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3059","DOI":"10.1038\/onc.2016.437","article-title":"Blockade of the IL-6 trans-signalling\/STAT3 axis suppresses cachexia in Kras-induced lung adenocarcinoma","volume":"36","author":"Miller","year":"2017","journal-title":"Oncogene"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Konen, J.M., Rodriguez, B.L., Fradette, J.J., Gibson, L., Davis, D., Minelli, R., Peoples, M.D., Kovacs, J., Carugo, A., and Bristow, C. (2019). Ntrk1 promotes resistance to PD-1 checkpoint blockade in Mesenchymal Kras\/p53 mutant lung cancer. Cancers, 11.","DOI":"10.3390\/cancers11040462"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1002\/ijc.11681","article-title":"MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma","volume":"109","author":"Atkins","year":"2004","journal-title":"Int. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1016\/j.trsl.2015.02.008","article-title":"Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome","volume":"166","author":"Koelzer","year":"2015","journal-title":"Transl. Res."},{"key":"ref_68","first-page":"354","article-title":"Mutant KRAS Conversion of Conventional T Cells into Regulatory T Cells","volume":"4","author":"Zdanov","year":"2016","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"559","DOI":"10.1016\/j.ccell.2019.02.008","article-title":"KRAS-IRF2 Axis Drives Immune Suppression and Immune Therapy Resistance in Colorectal Cancer","volume":"35","author":"Liao","year":"2019","journal-title":"Cancer Cell"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"7280","DOI":"10.18632\/oncotarget.6906","article-title":"CXCR2 signaling regulates KRAS(G12D) -induced autocrine growth of pancreatic cancer","volume":"7","author":"Purohit","year":"2016","journal-title":"Oncotarget"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature25492","article-title":"TGF\u03b2 drives immune evasion in genetically reconstituted colon cancer metastasis","volume":"554","author":"Tauriello","year":"2018","journal-title":"Nature"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1016\/j.ccr.2012.04.024","article-title":"Oncogenic Kras-Induced GM-CSF Production Promotes the Development of Pancreatic Neoplasia","volume":"21","author":"Lee","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.ccr.2012.04.025","article-title":"Tumor-derived granulocyte-macrophage colony stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer","volume":"21","author":"Bayne","year":"2012","journal-title":"Cancer Cell"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1136\/gutjnl-2013-306271","article-title":"Targeted depletion of a MDSC subset unmasks pancreatic ductal adenocarcinoma to adaptive immunity","volume":"63","author":"Stromnes","year":"2014","journal-title":"Gut"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"3190","DOI":"10.1016\/j.celrep.2017.11.052","article-title":"Neutrophils and Snail Orchestrate the Establishment of a Pro-tumor Microenvironment in Lung Cancer","volume":"21","author":"Faget","year":"2017","journal-title":"Cell Rep."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"2629","DOI":"10.1158\/0008-5472.CAN-14-2921","article-title":"Chemotherapy-Derived Inflammatory Responses Accelerate the Formation of Immunosuppressive Myeloid Cells in the Tissue Microenvironment of Human Pancreatic Cancer","volume":"75","author":"Takeuchi","year":"2015","journal-title":"Cancer Res."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.3389\/fimmu.2019.01835","article-title":"The Dark Side of Fibroblasts: Cancer-Associated Fibroblasts as Mediators of Immunosuppression in the Tumor Microenvironment","volume":"10","author":"Monteran","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"414","DOI":"10.3389\/fimmu.2018.00414","article-title":"Alteration of the antitumor immune response by cancer-associated fibroblasts","volume":"9","author":"Ziani","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"4457","DOI":"10.1038\/onc.2017.65","article-title":"Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like","volume":"36","author":"Cohen","year":"2017","journal-title":"Oncogene"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"582","DOI":"10.1038\/nrc.2016.73","article-title":"The biology and function of fibroblasts in cancer","volume":"16","author":"Kalluri","year":"2016","journal-title":"Nat. Rev. Cancer"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3613","DOI":"10.1172\/JCI38988","article-title":"Targeting fibroblast activation protein inhibits tumor stromagenesis and growth in mice","volume":"119","author":"Santos","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/j.ccr.2014.04.021","article-title":"Stromal elements act to restrain, rather than support, pancreatic ductal adenocarcinoma","volume":"25","author":"Rhim","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"E3091","DOI":"10.1073\/pnas.1411679111","article-title":"Stromal response to Hedgehog signaling restrains pancreatic cancer progression","volume":"111","author":"Lee","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"14048","DOI":"10.1074\/jbc.M611089200","article-title":"Oncogenic KRAS activates hedgehog signaling pathway in pancreatic cancer cells","volume":"282","author":"Ji","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"639","DOI":"10.1172\/JCI59227","article-title":"Oncogenic Kras is required for both the initiation and maintenance of pancreatic cancer in mice","volume":"122","author":"Collins","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1016\/j.ccr.2014.04.005","article-title":"Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Diminished Survival","volume":"25","author":"Carstens","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"1640","DOI":"10.4161\/cbt.5.12.3354","article-title":"Identification of fibroblast heterogeneity in the tumor microenvironment","volume":"5","author":"Sugimoto","year":"2006","journal-title":"Cancer Biol. Ther."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"579","DOI":"10.1084\/jem.20162024","article-title":"Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer","volume":"214","author":"Biffi","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"910","DOI":"10.1016\/j.cell.2016.03.029","article-title":"Oncogenic KRAS Regulates Tumor Cell Signaling via Stromal Reciprocation","volume":"165","author":"Tape","year":"2016","journal-title":"Cell"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"4106","DOI":"10.1172\/JCI42754","article-title":"Inhibiting Cxcr2 disrupts tumor-stromal interactions and improves survival in a mouse model of pancreatic ductal adenocarcinoma","volume":"121","author":"Ijichi","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/s41389-018-0117-8","article-title":"Blocking CXCLs\u2013CXCR2 axis in tumor\u2014stromal interactions contributes to survival in a mouse model of pancreatic ductal adenocarcinoma through reduced cell invasion \/ migration and a shift of immune-in fl ammatory microenvironment","volume":"8","author":"Sano","year":"2019","journal-title":"Oncogenesis"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"20212","DOI":"10.1073\/pnas.1320318110","article-title":"Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer","volume":"110","author":"Feig","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"320","DOI":"10.1136\/gutjnl-2016-311585","article-title":"IL-6 and PD-L1 antibody blockade combination therapy reduces tumor progression in murine models of pancreatic cancer","volume":"67","author":"Mace","year":"2018","journal-title":"Gut"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"11786","DOI":"10.1074\/jbc.M112.438846","article-title":"Loss of the Transcription Factor GLI1 Identifies a Signaling Network in the Tumor Microenvironment Mediating KRAS","volume":"288","author":"Mills","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"796","DOI":"10.1158\/1078-0432.CCR-18-0368","article-title":"KRAS G12C NSCLC models are sensitive to direct targeting of KRAS in combination with PI3K inhibition","volume":"25","author":"Misale","year":"2019","journal-title":"Clin. Cancer Res."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/12\/2010\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:42:01Z","timestamp":1760190121000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/12\/2010"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,12,13]]},"references-count":95,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["cancers11122010"],"URL":"https:\/\/doi.org\/10.3390\/cancers11122010","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,12,13]]}}}