{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T15:07:35Z","timestamp":1785424055984,"version":"3.56.0"},"reference-count":141,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,4]],"date-time":"2026-07-04T00:00:00Z","timestamp":1783123200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Science and Technology Council, Taiwan","award":["NSTC 112-2320-B-039-019"],"award-info":[{"award-number":["NSTC 112-2320-B-039-019"]}]},{"award":["NSTC 112-2320-B-039-019"],"award-info":[{"award-number":["NSTC 112-2320-B-039-019"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100012544","name":"China Medical University, Taiwan","doi-asserted-by":"crossref","award":["CMU113-MF-01"],"award-info":[{"award-number":["CMU113-MF-01"]}],"id":[{"id":"10.13039\/501100012544","id-type":"DOI","asserted-by":"crossref"}]},{"award":["CMU113-MF-01"],"award-info":[{"award-number":["CMU113-MF-01"]}],"id":[{"id":"https:\/\/ror.org\/00v408z34","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004737","name":"National Health Research Institutes, Taiwan","doi-asserted-by":"crossref","award":["NHRI-EX115-11403BI"],"award-info":[{"award-number":["NHRI-EX115-11403BI"]}],"id":[{"id":"10.13039\/501100004737","id-type":"DOI","asserted-by":"crossref"}]},{"award":["NHRI-EX115-11403BI"],"award-info":[{"award-number":["NHRI-EX115-11403BI"]}],"id":[{"id":"https:\/\/ror.org\/02r6fpx29","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Solid tumors frequently experience hypoxia during tumor progression, resulting in profound metabolic alterations. This phenomenon is particularly pronounced in clear-cell renal cell carcinoma (ccRCC) because of loss of the von Hippel\u2013Lindau (VHL) tumor suppressor gene and constitutive activation of hypoxia-inducible factor (HIF) signaling. ccRCC is the most common subtype of kidney cancer, and durable therapeutic responses remain limited despite advances in immune checkpoint inhibition. Owing to its strong pseudohypoxic phenotype and extensive metabolic rewiring, ccRCC is widely regarded as a metabolic disease. These alterations generate a unique immune landscape characterized by abundant immune-cell infiltration together with profound T-cell dysfunction and exhaustion. This paradoxical \u201cimmune-hot yet immunosuppressed\u201d phenotype is largely driven by hypoxia-associated immunometabolic reprogramming within tumor cells and the tumor microenvironment (TME). Several metabolic pathways are critically involved in this process, including lactate acidosis, arginine (Arg) depletion, tryptophan (Trp) depletion, kynurenine (Kyn)-mediated T-cell exhaustion, and adenosine-driven immune suppression. This review summarizes the current understanding of hypoxia-driven immunometabolic interactions in ccRCC and discusses how targeting these pathways may improve future therapeutic strategies against this aggressive malignancy.<\/jats:p>","DOI":"10.3390\/ijms27136021","type":"journal-article","created":{"date-parts":[[2026,7,6]],"date-time":"2026-07-06T13:43:14Z","timestamp":1783345394000},"page":"6021","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immunometabolic Stress and Immune Suppression in Clear-Cell Renal Cell Carcinoma: Perspectives in Therapeutic Strategy"],"prefix":"10.3390","volume":"27","author":[{"given":"Tuong-Vi","family":"Nguyen","sequence":"first","affiliation":[{"name":"Department of Biomedical Sciences and Engineering, National Central University, 300 Zhongda Rd., Taoyuan 320317, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2308-4297","authenticated-orcid":false,"given":"Tien","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Engineering, National Central University, 300 Zhongda Rd., Taoyuan 320317, Taiwan"},{"name":"Graduate Institute of Biomedical Sciences, China Medical University (Taiwan), 91 Hsueh-Shih Rd., Taichung 404333, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"17009","DOI":"10.1038\/nrdp.2017.9","article-title":"Renal cell carcinoma","volume":"3","author":"Hsieh","year":"2017","journal-title":"Nat. Rev. Dis. Primers"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"79","DOI":"10.14740\/wjon1279","article-title":"Epidemiology of Renal Cell Carcinoma","volume":"11","author":"Padala","year":"2020","journal-title":"World J. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"592","DOI":"10.1038\/nrc2442","article-title":"Modes of resistance to anti-angiogenic therapy","volume":"8","author":"Bergers","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1038\/s41392-023-01460-1","article-title":"Angiogenic signaling pathways and anti-angiogenic therapy for cancer","volume":"8","author":"Liu","year":"2023","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1056\/NEJMoa1510665","article-title":"Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma","volume":"373","author":"Motzer","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1056\/NEJMoa1200690","article-title":"Safety, activity, and immune correlates of anti-PD-1 antibody in cancer","volume":"366","author":"Topalian","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1056\/NEJMoa1712126","article-title":"Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma","volume":"378","author":"Motzer","year":"2018","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1056\/NEJMoa1816714","article-title":"Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma","volume":"380","author":"Rini","year":"2019","journal-title":"N. Engl. J. Med."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"The Cancer Genome Atlas Research Network (2013). Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature, 499, 43\u201349.","DOI":"10.1038\/nature12222"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"860","DOI":"10.1038\/ng.2699","article-title":"Integrated molecular analysis of clear-cell renal cell carcinoma","volume":"45","author":"Sato","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1016\/j.semcancer.2012.06.001","article-title":"The VHL\/HIF axis in clear cell renal carcinoma","volume":"23","author":"Shen","year":"2013","journal-title":"Semin. Cancer Biol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.semcancer.2008.11.009","article-title":"Regulation of cancer cell metabolism by hypoxia-inducible factor 1","volume":"19","author":"Semenza","year":"2009","journal-title":"Semin. Cancer Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1038\/s41420-025-02479-9","article-title":"The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma","volume":"11","author":"Zhang","year":"2025","journal-title":"Cell Death Discov."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Kim, M.C., Jin, Z., Kolb, R., Borcherding, N., Chatzkel, J.A., Falzarano, S.M., and Zhang, W. (2021). Updates on Immunotherapy and Immune Landscape in Renal Clear Cell Carcinoma. Cancers, 13.","DOI":"10.3390\/cancers13225856"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100558","DOI":"10.1016\/j.modpat.2024.100558","article-title":"Immune Phenotype-Genotype Associations in Primary Clear Cell Renal Cell Carcinoma and Matched Metastatic Tissue","volume":"37","author":"Sobottka","year":"2024","journal-title":"Mod. Pathol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1016\/j.ccell.2021.10.001","article-title":"Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma","volume":"39","author":"Au","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1038\/s42003-020-01625-6","article-title":"Mapping the immune environment in clear cell renal carcinoma by single-cell genomics","volume":"4","author":"Borcherding","year":"2021","journal-title":"Commun. Biol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1016\/j.cell.2017.04.016","article-title":"An Immune Atlas of Clear Cell Renal Cell Carcinoma","volume":"169","author":"Chevrier","year":"2017","journal-title":"Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1016\/j.ccell.2021.02.013","article-title":"Progressive immune dysfunction with advancing disease stage in renal cell carcinoma","volume":"39","author":"Braun","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1837","DOI":"10.1152\/physrev.00039.2021","article-title":"Lymphatic vessels in cancer","volume":"102","author":"Dieterich","year":"2022","journal-title":"Physiol. Rev."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"655","DOI":"10.1038\/s41581-021-00438-y","article-title":"The lymphatics in kidney health and disease","volume":"17","author":"Donnan","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Russell, P.S., Hong, J., Windsor, J.A., Itkin, M., and Phillips, A.R.J. (2019). Renal Lymphatics: Anatomy, Physiology, and Clinical Implications. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.00251"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1158\/0008-5472.CAN-16-3088","article-title":"Sunitinib Stimulates Expression of VEGFC by Tumor Cells and Promotes Lymphangiogenesis in Clear Cell Renal Cell Carcinomas","volume":"77","author":"Dufies","year":"2017","journal-title":"Cancer Res."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Dieterich, L.C., Ikenberg, K., Cetintas, T., Kapaklikaya, K., Hutmacher, C., and Detmar, M. (2017). Tumor-Associated Lymphatic Vessels Upregulate PDL1 to Inhibit T-Cell Activation. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00066"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1186\/s12967-026-07713-1","article-title":"Combining spatial and single-cell transcriptome data to analyze tertiary lymphoid structures in clear cell renal cell carcinoma reveals prognostic biomarkers","volume":"24","author":"Li","year":"2026","journal-title":"J. Transl. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"e006667","DOI":"10.1136\/jitc-2023-006667","article-title":"Heterogeneity in tertiary lymphoid structures predicts distinct prognosis and immune microenvironment characterizations of clear cell renal cell carcinoma","volume":"11","author":"Xu","year":"2023","journal-title":"J. Immunother. Cancer"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.1158\/2159-8290.CD-18-1354","article-title":"The Metabolic Basis of Kidney Cancer","volume":"9","author":"Linehan","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.ccell.2015.12.004","article-title":"An Integrated Metabolic Atlas of Clear Cell Renal Cell Carcinoma","volume":"29","author":"Hakimi","year":"2016","journal-title":"Cancer Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9519","DOI":"10.1074\/jbc.M010144200","article-title":"Regulation of glut1 mRNA by hypoxia-inducible factor-1. Interaction between H-ras and hypoxia","volume":"276","author":"Chen","year":"2001","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1677\/joe.1.05599","article-title":"Induction of glucose transporter 1 expression through hypoxia-inducible factor 1alpha under hypoxic conditions in trophoblast-derived cells","volume":"183","author":"Hayashi","year":"2004","journal-title":"J. Endocrinol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"100077","DOI":"10.1016\/j.cellin.2023.100077","article-title":"Hexokinases in cancer and other pathologies","volume":"2","author":"Guo","year":"2023","journal-title":"Cell Insight"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1038\/nature10602","article-title":"Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia","volume":"481","author":"Metallo","year":"2012","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"7381","DOI":"10.1128\/MCB.00440-07","article-title":"Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1","volume":"27","author":"Kim","year":"2007","journal-title":"Mol. Cell Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"372","DOI":"10.1016\/j.cmet.2013.02.002","article-title":"In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation","volume":"17","author":"Gameiro","year":"2013","journal-title":"Cell Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"865","DOI":"10.1038\/nrc2502","article-title":"The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer","volume":"8","author":"Kaelin","year":"2008","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e93411","DOI":"10.1172\/jci.insight.93411","article-title":"Mitochondrial dysregulation and glycolytic insufficiency functionally impair CD8 T cells infiltrating human renal cell carcinoma","volume":"2","author":"Siska","year":"2017","journal-title":"JCI Insight"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1038\/s41423-021-00727-3","article-title":"The therapeutic implications of immunosuppressive tumor aerobic glycolysis","volume":"19","author":"Reinfeld","year":"2022","journal-title":"Cell Mol. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1239","DOI":"10.1016\/j.cell.2013.05.016","article-title":"Posttranscriptional control of T cell effector function by aerobic glycolysis","volume":"153","author":"Chang","year":"2013","journal-title":"Cell"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/imm.12655","article-title":"T-cell metabolism governing activation, proliferation and differentiation; a modular view","volume":"150","author":"Dimeloe","year":"2017","journal-title":"Immunology"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/j.ccell.2022.01.001","article-title":"Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments","volume":"40","author":"Kumagai","year":"2022","journal-title":"Cancer Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/s41586-020-03045-2","article-title":"Metabolic support of tumour-infiltrating regulatory T cells by lactic acid","volume":"591","author":"Watson","year":"2021","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1282","DOI":"10.1016\/j.cmet.2016.12.018","article-title":"Foxp3 Reprograms T Cell Metabolism to Function in Low-Glucose, High-Lactate Environments","volume":"25","author":"Angelin","year":"2017","journal-title":"Cell Metab."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e89160","DOI":"10.1172\/jci.insight.89160","article-title":"Foxp3 drives oxidative phosphorylation and protection from lipotoxicity","volume":"2","author":"Howie","year":"2017","journal-title":"JCI Insight"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"a040584","DOI":"10.1101\/cshperspect.a040584","article-title":"Amino Acid Metabolism","volume":"13","author":"Chandel","year":"2021","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2791S","DOI":"10.1093\/jn\/134.10.2791S","article-title":"Renal arginine metabolism","volume":"134","author":"Brosnan","year":"2004","journal-title":"J. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"F95","DOI":"10.1152\/ajprenal.00487.2009","article-title":"In vivo renal arginine release is impaired throughout development of chronic kidney disease","volume":"298","author":"Chen","year":"2010","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"3379","DOI":"10.1093\/nar\/28.17.3379","article-title":"Structural basis of polyamine-DNA recognition: Spermidine and spermine interactions with genomic B-DNAs of different GC content probed by Raman spectroscopy","volume":"28","author":"Deng","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"eabc8929","DOI":"10.1126\/sciadv.abc8929","article-title":"Polyamines drive myeloid cell survival by buffering intracellular pH to promote immunosuppression in glioblastoma","volume":"7","author":"Miska","year":"2021","journal-title":"Sci. Adv."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1781","DOI":"10.2215\/CJN.08750812","article-title":"Urine-concentrating mechanism in the inner medulla: Function of the thin limbs of the loops of Henle","volume":"9","author":"Dantzler","year":"2014","journal-title":"Clin. J. Am. Soc. Nephrol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1016\/j.cmet.2018.04.009","article-title":"Arginase 2 Suppresses Renal Carcinoma Progression via Biosynthetic Cofactor Pyridoxal Phosphate Depletion and Increased Polyamine Toxicity","volume":"27","author":"Ochocki","year":"2018","journal-title":"Cell Metab."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s40170-021-00271-8","article-title":"ASS1 and ASL suppress growth in clear cell renal cell carcinoma via altered nitrogen metabolism","volume":"9","author":"Khare","year":"2021","journal-title":"Cancer Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.cell.2016.02.035","article-title":"The CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway","volume":"165","author":"Chantranupong","year":"2016","journal-title":"Cell"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1038\/nature19079","article-title":"Mechanism of arginine sensing by CASTOR1 upstream of mTORC1","volume":"536","author":"Saxton","year":"2016","journal-title":"Nature"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1126\/science.1257132","article-title":"Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1","volume":"347","author":"Wang","year":"2015","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1038\/s41416-018-0333-1","article-title":"Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression","volume":"120","author":"Groth","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1038\/s41392-021-00670-9","article-title":"Myeloid-derived suppressor cells as immunosuppressive regulators and therapeutic targets in cancer","volume":"6","author":"Li","year":"2021","journal-title":"Signal Transduct. Target Ther."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1158\/0008-5472.CAN-14-1491","article-title":"l-Arginine depletion blunts antitumor T-cell responses by inducing myeloid-derived suppressor cells","volume":"75","author":"Fletcher","year":"2015","journal-title":"Cancer Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"21123","DOI":"10.1074\/jbc.M110675200","article-title":"Regulation of T cell receptor CD3zeta chain expression by L-arginine","volume":"277","author":"Rodriguez","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.cellimm.2005.01.004","article-title":"L-Arginine modulates CD3zeta expression and T cell function in activated human T lymphocytes","volume":"232","author":"Zea","year":"2004","journal-title":"Cell Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/j.cell.2016.09.031","article-title":"L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity","volume":"167","author":"Geiger","year":"2016","journal-title":"Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/j.immuni.2005.03.013","article-title":"GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase","volume":"22","author":"Munn","year":"2005","journal-title":"Immunity"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Chen, M., Nie, Z., Huang, D., Gao, Y., Cao, H., Zheng, L., and Zhang, S. (2022). Development of a polyamine gene expression score for predicting prognosis and treatment response in clear cell renal cell carcinoma. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1048204"},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"di Meo, N.A., Lasorsa, F., Rutigliano, M., Loizzo, D., Ferro, M., Stella, A., Bizzoca, C., Vincenti, L., Pandolfo, S.D., and Autorino, R. (2022). Renal Cell Carcinoma as a Metabolic Disease: An Update on Main Pathways, Potential Biomarkers, and Therapeutic Targets. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232214360"},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Gong, Z., Lin, H., Wang, J., Hua, J., Wei, J., Chen, W., Luo, J., Pang, J., and Chen, X. (2025). A robust ammonia metabolism gene signature identified by machine learning predicts prognosis and immunotherapy response in clear cell renal cell carcinoma. Front. Oncol., 15.","DOI":"10.3389\/fonc.2025.1709096"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"e2103240118","DOI":"10.1073\/pnas.2103240118","article-title":"Single-cell analyses of renal cell cancers reveal insights into tumor microenvironment, cell of origin, and therapy response","volume":"118","author":"Zhang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1038\/s41416-019-0664-6","article-title":"The therapeutic potential of targeting tryptophan catabolism in cancer","volume":"122","author":"Opitz","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1038\/s44324-025-00067-0","article-title":"The role of NAD(+) metabolism and its modulation of mitochondria in aging and disease","volume":"3","author":"Yusri","year":"2025","journal-title":"npj Metab. Health Dis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/s12276-023-01028-7","article-title":"Immune regulation through tryptophan metabolism","volume":"55","author":"Seo","year":"2023","journal-title":"Exp. Mol. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/s41416-019-0614-3","article-title":"Nongenic cancer-risk SNPs affect oncogenes, tumour-suppressor genes, and immune function","volume":"122","author":"Fagny","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1158\/2326-6066.CIR-16-0400","article-title":"Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance","volume":"5","author":"Hennequart","year":"2017","journal-title":"Cancer Immunol. Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.it.2016.01.002","article-title":"IDO in the Tumor Microenvironment: Inflammation, Counter-Regulation, and Tolerance","volume":"37","author":"Munn","year":"2016","journal-title":"Trends Immunol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"946","DOI":"10.1016\/j.molmed.2021.07.006","article-title":"The kynurenine pathway in chronic diseases: A compensatory mechanism or a driving force?","volume":"27","author":"Joisten","year":"2021","journal-title":"Trends Mol. Med."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1038\/ni1283","article-title":"Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling","volume":"7","author":"Collins","year":"2006","journal-title":"Nat. Immunol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"6752","DOI":"10.4049\/jimmunol.176.11.6752","article-title":"The combined effects of tryptophan starvation and tryptophan catabolites down-regulate T cell receptor zeta-chain and induce a regulatory phenotype in naive T cells","volume":"176","author":"Fallarino","year":"2006","journal-title":"J. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1981","DOI":"10.1016\/j.immuni.2022.10.006","article-title":"Regulatory T cells as metabolic sensors","volume":"55","author":"Procaccini","year":"2022","journal-title":"Immunity"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"eaax8189","DOI":"10.1126\/sciimmunol.aax8189","article-title":"GCN2 drives macrophage and MDSC function and immunosuppression in the tumor microenvironment","volume":"4","author":"Halaby","year":"2019","journal-title":"Sci. Immunol."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Pichler, R., Siska, P.J., Tymoszuk, P., Martowicz, A., Untergasser, G., Mayr, R., Weber, F., Seeber, A., Kocher, F., and Barth, D.A. (2023). A chemokine network of T cell exhaustion and metabolic reprogramming in renal cell carcinoma. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1095195"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"1424","DOI":"10.1016\/j.cmet.2023.06.005","article-title":"Immunometabolic coevolution defines unique microenvironmental niches in ccRCC","volume":"35","author":"Tang","year":"2023","journal-title":"Cell Metab."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"480","DOI":"10.1016\/j.ccell.2018.02.005","article-title":"Tumor-Repopulating Cells Induce PD-1 Expression in CD8(+) T Cells by Transferring Kynurenine and AhR Activation","volume":"33","author":"Liu","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.1038\/s41467-020-17750-z","article-title":"Blockade of the AHR restricts a Treg-macrophage suppressive axis induced by L-Kynurenine","volume":"11","author":"Campesato","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"3190","DOI":"10.4049\/jimmunol.0903670","article-title":"An interaction between kynurenine and the aryl hydrocarbon receptor can generate regulatory T cells","volume":"185","author":"Mezrich","year":"2010","journal-title":"J. Immunol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"12150","DOI":"10.1038\/s41598-019-48635-x","article-title":"Exhaustion of CD4+ T-cells mediated by the Kynurenine Pathway in Melanoma","volume":"9","author":"Morikawa","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"461.e15","DOI":"10.1016\/j.urolonc.2017.02.011","article-title":"Activation of the kynurenine pathway predicts poor outcome in patients with clear cell renal cell carcinoma","volume":"35","author":"Lucarelli","year":"2017","journal-title":"Urol. Oncol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1186\/s12967-025-06276-x","article-title":"IDO1 inhibition enhances CLDN18.2-CAR-T cell therapy in gastrointestinal cancers by overcoming kynurenine-mediated metabolic suppression in the tumor microenvironment","volume":"23","author":"Wu","year":"2025","journal-title":"J. Transl. Med."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2055703","DOI":"10.1080\/2162402X.2022.2055703","article-title":"Superior antitumor immunotherapy efficacy of kynureninase modified CAR-T cells through targeting kynurenine metabolism","volume":"11","author":"Yang","year":"2022","journal-title":"Oncoimmunology"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"1261","DOI":"10.1158\/1535-7163.MCT-21-0984","article-title":"Discovery and Characterization of a Novel Aryl Hydrocarbon Receptor Inhibitor, IK-175, and Its Inhibitory Activity on Tumor Immune Suppression","volume":"21","author":"McGovern","year":"2022","journal-title":"Mol. Cancer Ther."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1038\/cdd.2013.75","article-title":"Molecular mechanisms of ATP secretion during immunogenic cell death","volume":"21","author":"Martins","year":"2014","journal-title":"Cell Death Differ."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"855","DOI":"10.1158\/0008-5472.CAN-09-3566","article-title":"Tumor cell death and ATP release prime dendritic cells and efficient anticancer immunity","volume":"70","author":"Aymeric","year":"2010","journal-title":"Cancer Res."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1016\/j.bbamcr.2008.01.024","article-title":"Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade","volume":"1783","author":"Yegutkin","year":"2008","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1111\/imr.12528","article-title":"The ectonucleotidases CD39 and CD73: Novel checkpoint inhibitor targets","volume":"276","author":"Allard","year":"2017","journal-title":"Immunol. Rev."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1172\/JCI0215337","article-title":"Ecto-5\u2032-nucleotidase (CD73) regulation by hypoxia-inducible factor-1 mediates permeability changes in intestinal epithelia","volume":"110","author":"Synnestvedt","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"e001467","DOI":"10.1136\/jitc-2020-001467","article-title":"Prognostic significance and immune correlates of CD73 expression in renal cell carcinoma","volume":"8","author":"Tripathi","year":"2020","journal-title":"J. Immunother. Cancer"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"3623","DOI":"10.1021\/jm4011669","article-title":"Adenosine A2A receptor as a drug discovery target","volume":"57","author":"Lim","year":"2014","journal-title":"J. Med. Chem."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"916","DOI":"10.1038\/414916a","article-title":"Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage","volume":"414","author":"Ohta","year":"2001","journal-title":"Nature"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"13132","DOI":"10.1073\/pnas.0605251103","article-title":"A2A adenosine receptor protects tumors from antitumor T cells","volume":"103","author":"Ohta","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1124\/jpet.115.230003","article-title":"Ligand-Independent Adenosine A2B Receptor Constitutive Activity as a Promoter of Prostate Cancer Cell Proliferation","volume":"357","author":"Vecchio","year":"2016","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"2009","DOI":"10.1007\/s00262-020-02843-x","article-title":"Increased expression of adenosine 2A receptors in metastatic renal cell carcinoma is associated with poorer response to anti-vascular endothelial growth factor agents and anti-PD-1\/Anti-CTLA4 antibodies and shorter survival","volume":"70","author":"Kamai","year":"2021","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_98","first-page":"995","article-title":"Adenosine signaling in tumor-associated macrophages and targeting adenosine signaling for cancer therapy","volume":"21","author":"Yang","year":"2024","journal-title":"Cancer Biol. Med."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"7250","DOI":"10.1158\/0008-5472.CAN-13-3583","article-title":"Myeloid expression of adenosine A2A receptor suppresses T and NK cell responses in the solid tumor microenvironment","volume":"74","author":"Cekic","year":"2014","journal-title":"Cancer Res."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"2458936","DOI":"10.1080\/21645515.2025.2458936","article-title":"Neoantigen mRNA vaccines and A(2)A receptor antagonism: A strategy to enhance T cell immunity","volume":"21","author":"Imani","year":"2025","journal-title":"Hum. Vaccin. Immunother."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1951","DOI":"10.1016\/j.apsb.2023.12.004","article-title":"The inhibitory effect of adenosine on tumor adaptive immunity and intervention strategies","volume":"14","author":"Wang","year":"2024","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"623","DOI":"10.4049\/jimmunol.1601686","article-title":"Cutting Edge: Adenosine A2a Receptor Signals Inhibit Germinal Center T Follicular Helper Cell Differentiation during the Primary Response to Vaccination","volume":"198","author":"Schmiel","year":"2017","journal-title":"J. Immunol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1593\/neo.131748","article-title":"Blockade of A2b adenosine receptor reduces tumor growth and immune suppression mediated by myeloid-derived suppressor cells in a mouse model of melanoma","volume":"15","author":"Iannone","year":"2013","journal-title":"Neoplasia"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"676","DOI":"10.4049\/jimmunol.1003884","article-title":"Cancer exosomes express CD39 and CD73, which suppress T cells through adenosine production","volume":"187","author":"Clayton","year":"2011","journal-title":"J. Immunol."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"709","DOI":"10.1038\/nrc.2017.86","article-title":"Targeting immunosuppressive adenosine in cancer","volume":"17","author":"Vijayan","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Takeda, M., Akamatsu, S., Kita, Y., Goto, T., and Kobayashi, T. (2023). The Roles of Extracellular Vesicles in the Progression of Renal Cell Carcinoma and Their Potential for Future Clinical Application. Nanomaterials, 13.","DOI":"10.3390\/nano13101611"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s002400050001","article-title":"Interstitial fluid pressure is increased in renal cell carcinoma xenografts","volume":"28","author":"Rohde","year":"2000","journal-title":"Urol. Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1016\/S0360-3016(98)00512-4","article-title":"The relationship between elevated interstitial fluid pressure and blood flow in tumors: A bioengineering analysis","volume":"43","author":"Milosevic","year":"1999","journal-title":"Int. J. Radiat. Oncol. Biol. Phys."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"806","DOI":"10.1038\/nrc1456","article-title":"High interstitial fluid pressure\u2014An obstacle in cancer therapy","volume":"4","author":"Heldin","year":"2004","journal-title":"Nat. Rev. Cancer"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.jtbi.2012.11.031","article-title":"The effect of interstitial pressure on tumor growth: Coupling with the blood and lymphatic vascular systems","volume":"320","author":"Wu","year":"2013","journal-title":"J. Theor. Biol."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"eaaz0868","DOI":"10.1126\/science.aaz0868","article-title":"Physical traits of cancer","volume":"370","author":"Nia","year":"2020","journal-title":"Science"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"1015","DOI":"10.1016\/j.chembiol.2023.08.011","article-title":"Tumor microenvironmental nutrients, cellular responses, and cancer","volume":"30","author":"Lobel","year":"2023","journal-title":"Cell Chem. Biol."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"RP95652","DOI":"10.7554\/eLife.95652","article-title":"Metabolite profiling of human renal cell carcinoma reveals tissue-origin dominance in nutrient availability","volume":"13","author":"Abbott","year":"2024","journal-title":"Elife"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1126\/science.1104819","article-title":"Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy","volume":"307","author":"Jain","year":"2005","journal-title":"Science"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"17561","DOI":"10.1073\/pnas.1215397109","article-title":"Vascular normalizing doses of antiangiogenic treatment reprogram the immunosuppressive tumor microenvironment and enhance immunotherapy","volume":"109","author":"Huang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1038\/s41416-021-01330-z","article-title":"Vascular normalisation as the stepping stone into tumour microenvironment transformation","volume":"125","author":"Magnussen","year":"2021","journal-title":"Br. J. Cancer"},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"oyag193","DOI":"10.1093\/oncolo\/oyag193","article-title":"From prevention to progression: Can belzutifan-based strategies deliver across the RCC disease continuum?","volume":"31","author":"Beckermann","year":"2026","journal-title":"Oncologist"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"710","DOI":"10.1056\/NEJMoa2313906","article-title":"Belzutifan versus Everolimus for Advanced Renal-Cell Carcinoma","volume":"391","author":"Choueiri","year":"2024","journal-title":"N. Engl. J. Med."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"1540","DOI":"10.1158\/1078-0432.CCR-21-2972","article-title":"Telaglenastat Plus Cabozantinib or Everolimus for Advanced or Metastatic Renal Cell Carcinoma: An Open-Label Phase I Trial","volume":"28","author":"Tannir","year":"2022","journal-title":"Clin. Cancer Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"1411","DOI":"10.1001\/jamaoncol.2022.3511","article-title":"Efficacy and Safety of Telaglenastat Plus Cabozantinib vs Placebo Plus Cabozantinib in Patients With Advanced Renal Cell Carcinoma: The CANTATA Randomized Clinical Trial","volume":"8","author":"Tannir","year":"2022","journal-title":"JAMA Oncol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1158\/1078-0432.CCR-22-2263","article-title":"A Phase I Dose-escalation Study of AZD3965, an Oral Monocarboxylate Transporter 1 Inhibitor, in Patients with Advanced Cancer","volume":"29","author":"Halford","year":"2023","journal-title":"Clin. Cancer Res."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"2285","DOI":"10.1158\/1535-7163.MCT-17-1253","article-title":"Preclinical Efficacy of the Novel Monocarboxylate Transporter 1 Inhibitor BAY-8002 and Associated Markers of Resistance","volume":"17","author":"Quanz","year":"2018","journal-title":"Mol. Cancer Ther."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"108057","DOI":"10.1016\/j.phrs.2025.108057","article-title":"Drug targeting of the monocarboxylate transporter MCT4 is a novel treatment strategy for metastatic ccRCC","volume":"222","author":"Stuhler","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1038\/nchembio.2143","article-title":"Metabolic plasticity underpins innate and acquired resistance to LDHA inhibition","volume":"12","author":"Boudreau","year":"2016","journal-title":"Nat. Chem. Biol."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2037","DOI":"10.1073\/pnas.0914433107","article-title":"Inhibition of lactate dehydrogenase A induces oxidative stress and inhibits tumor progression","volume":"107","author":"Le","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_126","doi-asserted-by":"crossref","unstructured":"Lara, P.N., Villanueva, L., Ibanez, C., Erman, M., Lee, J.L., Heinrich, D., Lipatov, O.N., Gedye, C., Gokmen, E., and Acevedo, A. (2024). A randomized, open-label, phase 3 trial of pembrolizumab plus epacadostat versus sunitinib or pazopanib as first-line treatment for metastatic renal cell carcinoma (KEYNOTE-679\/ECHO-302). BMC Cancer, 23.","DOI":"10.1186\/s12885-023-10971-7"},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1158\/1078-0432.CCR-25-2013","article-title":"IK-175, an Oral Aryl Hydrocarbon Receptor Inhibitor, Alone and with Nivolumab in Patients with Advanced Solid Tumors and Urothelial Carcinoma","volume":"32","author":"Aggen","year":"2026","journal-title":"Clin. Cancer Res."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"e000249","DOI":"10.1136\/bmjonc-2023-000249","article-title":"First-in-human phase 1 study of the arginase inhibitor INCB001158 alone or combined with pembrolizumab in patients with advanced or metastatic solid tumours","volume":"3","author":"Naing","year":"2024","journal-title":"BMJ Oncol."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1001\/jamaoncol.2023.6789","article-title":"Pegargiminase Plus First-Line Chemotherapy in Patients With Nonepithelioid Pleural Mesothelioma: The ATOMIC-Meso Randomized Clinical Trial","volume":"10","author":"Szlosarek","year":"2024","journal-title":"JAMA Oncol."},{"key":"ref_130","doi-asserted-by":"crossref","unstructured":"Chu, Y.D., Lai, M.W., and Yeh, C.T. (2023). Unlocking the Potential of Arginine Deprivation Therapy: Recent Breakthroughs and Promising Future for Cancer Treatment. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241310668"},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"2443","DOI":"10.1007\/s00262-023-03430-6","article-title":"First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors","volume":"72","author":"Bendell","year":"2023","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1158\/2159-8290.CD-19-0980","article-title":"Adenosine 2A Receptor Blockade as an Immunotherapy for Treatment-Refractory Renal Cell Cancer","volume":"10","author":"Fong","year":"2020","journal-title":"Cancer Discov."},{"key":"ref_133","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1038\/s41586-025-09539-1","article-title":"Proteotoxic stress response drives T cell exhaustion and immune evasion","volume":"647","author":"Wang","year":"2025","journal-title":"Nature"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"442","DOI":"10.1038\/s41588-024-01662-5","article-title":"Multi-omic profiling of clear cell renal cell carcinoma identifies metabolic reprogramming associated with disease progression","volume":"56","author":"Hu","year":"2024","journal-title":"Nat. Genet."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"311.e15","DOI":"10.1016\/j.urolonc.2018.03.014","article-title":"Monocarboxylate transporters MCT1 and MCT4 are independent prognostic biomarkers for the survival of patients with clear cell renal cell carcinoma and those receiving therapy targeting angiogenesis","volume":"36","author":"Cao","year":"2018","journal-title":"Urol. Oncol."},{"key":"ref_136","doi-asserted-by":"crossref","first-page":"2530","DOI":"10.1200\/JCO.1999.17.8.2530","article-title":"Survival and prognostic stratification of 670 patients with advanced renal cell carcinoma","volume":"17","author":"Motzer","year":"1999","journal-title":"J. Clin. Oncol."},{"key":"ref_137","doi-asserted-by":"crossref","first-page":"5794","DOI":"10.1200\/JCO.2008.21.4809","article-title":"Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study","volume":"27","author":"Heng","year":"2009","journal-title":"J. Clin. Oncol."},{"key":"ref_138","doi-asserted-by":"crossref","first-page":"e008475","DOI":"10.1136\/jitc-2023-008475","article-title":"Neoadjuvant toripalimab combined with axitinib in patients with locally advanced clear cell renal cell carcinoma: A single-arm, phase II trial","volume":"12","author":"Huang","year":"2024","journal-title":"J. Immunother. Cancer"},{"key":"ref_139","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1111\/cas.13560","article-title":"High IDO-1 expression in tumor endothelial cells is associated with response to immunotherapy in metastatic renal cell carcinoma","volume":"109","author":"Seeber","year":"2018","journal-title":"Cancer Sci."},{"key":"ref_140","doi-asserted-by":"crossref","first-page":"4346","DOI":"10.1038\/s41467-019-12361-9","article-title":"Metabolomic adaptations and correlates of survival to immune checkpoint blockade","volume":"10","author":"Li","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_141","doi-asserted-by":"crossref","unstructured":"Quintas, G., Sanmartin, E., Garcia-Gimenez, A., Munoz-Langa, J., Collado, A., Suarez, C., Garcia Del Muro, X., Mendez-Vidal, M.J., Garcia-Sanchez, J., and Salvador-Coloma, C. (2026). Distinct protein and metabolic profiles in patients with advanced clear-cell renal cell carcinoma treated with sunitinib: A study of the Spanish oncology genitourinary group. Front. Oncol., 16.","DOI":"10.3389\/fonc.2026.1639330"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/6021\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T04:42:51Z","timestamp":1783399371000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/13\/6021"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,4]]},"references-count":141,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["ijms27136021"],"URL":"https:\/\/doi.org\/10.3390\/ijms27136021","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,4]]}}}