Hsieh JJ, Purdue MP, Signoretti S, Swanton C, Albiges L, Schmidinger M, et al. Renal cell carcinoma. Nat Rev Dis Prim. 2017;3:17009.
Google Scholar
Low G, Huang G, Fu W, Moloo Z, Girgis S. Review of renal cell carcinoma and its common subtypes in radiology. World J Radiol. 2016;8:484–500.
Google Scholar
Bellin MF, Valente C, Bekdache O, Maxwell F, Balasa C, Savignac A, et al. Update on renal cell carcinoma diagnosis with novel imaging approaches. Cancers. 2024;16:1926.
Bahadoram S, Davoodi M, Hassanzadeh S, Bahadoram M, Barahman M, Mafakher L. Renal cell carcinoma: an overview of the epidemiology, diagnosis, and treatment. G Ital Nefrol. 2022;39:2022-vol3.
Yang J, Wang K, Yang Z. Treatment strategies for clear cell renal cell carcinoma: Past, present and future. Front Oncol. 2023;13:1133832.
Google Scholar
Makhov P, Joshi S, Ghatalia P, Kutikov A, Uzzo RG, Kolenko VM. Resistance to systemic therapies in clear cell renal cell carcinoma: mechanisms and management strategies. Mol Cancer Ther. 2018;17:1355–64.
Google Scholar
Patel HD, Gupta M, Joice GA, Srivastava A, Alam R, Allaf ME, et al. Clinical stage migration and survival for renal cell carcinoma in the United States. Eur Urol Oncol. 2019;2:343–8.
Google Scholar
Samnani S, Sachedina F, Gupta M, Guo E, Navani V. Mechanisms and clinical implications in renal carcinoma resistance: narrative review of immune checkpoint inhibitors. Cancer Drug Resist. 2023;6:416–29.
Google Scholar
The Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499:43–9.
Ricketts CJ, De Cubas AA, Fan H, Smith CC, Lang M, Reznik E, et al. The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. Cell Rep. 2018;23:313–26.e315.
Google Scholar
Goswami PR, Singh G, Patel T, Dave R. The WHO 2022 Classification of Renal Neoplasms (5th Edition): salient updates. Cureus. 2024;16:e58470.
Google Scholar
Moch H, Amin MB, Berney DM, Compérat EM, Gill AJ, Hartmann A, et al. The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours. Eur Urol. 2022;82:458–68.
Google Scholar
Turajlic S, Xu H, Litchfield K, Rowan A, Horswell S, Chambers T, et al. Deterministic evolutionary trajectories influence primary tumor growth: TRACERx renal. Cell. 2018;173:595–.e511.
Google Scholar
Turajlic S, Xu H, Litchfield K, Rowan A, Chambers T, Lopez JI, et al. Tracking cancer evolution reveals constrained routes to metastases: TRACERx renal. Cell. 2018;173:581–94.e512.
Google Scholar
Fernández-Sanromán Á, Fendler A, Tan BJY, Cattin A-L, Spencer C, Thompson R, et al. Tracking nongenetic evolution from primary to metastatic ccRCC: TRACERx renal. Cancer Discov. 2025;15:530–52.
Google Scholar
Linehan WM, Srinivasan R, Schmidt LS. The genetic basis of kidney cancer: a metabolic disease. Nat Rev Urol. 2010;7:277–85.
Google Scholar
Kaelin WG Jr. The von Hippel-Lindau tumour suppressor protein: O2 sensing and cancer. Nat Rev Cancer. 2008;8:865–73.
Google Scholar
Clark DJ, Dhanasekaran SM, Petralia F, Pan J, Song X, Hu Y, et al. Integrated proteogenomic characterization of clear cell renal cell carcinoma. Cell. 2019;179:964–83.e931.
Google Scholar
Choueiri TK, Kaelin WG Jr. Targeting the HIF2-VEGF axis in renal cell carcinoma. Nat Med. 2020;26:1519–30.
Google Scholar
Braun DA, Hou Y, Bakouny Z, Ficial M, Sant’ Angelo M, Forman J, et al. Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma. Nat Med. 2020;26:909–18.
Google Scholar
Bi K, He MX, Bakouny Z, Kanodia A, Napolitano S, Wu J, et al. Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma. Cancer Cell. 2021;39:649–61.e645.
Google Scholar
Linehan WM, Ricketts CJ. The Cancer Genome Atlas of renal cell carcinoma: findings and clinical implications. Nat Rev Urol. 2019;16:539–52.
Google Scholar
Mohanty SK, Lobo A, Cheng L. The 2022 revision of the World Health Organization classification of tumors of the urinary system and male genital organs: advances and challenges. Hum Pathol. 2023;136:123–43.
Google Scholar
Alaghehbandan R, Siadat F, Trpkov K. What’s new in the WHO 2022 classification of kidney tumours?. Pathologica. 2022;115:8–22.
Google Scholar
Mitchell TJ, Turajlic S, Rowan A, Nicol D, Farmery JHR, O’Brien T, et al. Timing the landmark events in the evolution of clear cell renal cell cancer: TRACERx renal. Cell. 2018;173:611–23.e617.
Google Scholar
Gerlinger M, Rowan AJ, Horswell S, Math M, Larkin J, Endesfelder D, et al. Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med. 2012;366:883–92.
Google Scholar
Miao D, Margolis CA, Gao W, Voss MH, Li W, Martini DJ, et al. Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma. Science. 2018;359:801–6.
Google Scholar
Linehan WM, Spellman PT, Ricketts CJ, Creighton CJ, Fei SS, Davis C, et al. Comprehensive molecular characterization of papillary renal-cell carcinoma. N Engl J Med. 2016;374:135–45.
Google Scholar
Trpkov K, Hes O, Williamson SR, Adeniran AJ, Agaimy A, Alaghehbandan R, et al. New developments in existing WHO entities and evolving molecular concepts: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol. 2021;34:1392–424.
Google Scholar
Xiao Y, Clima R, Busch J, Rabien A, Kilic E, Villegas SL, et al. Decreased mitochondrial DNA content drives OXPHOS dysregulation in chromophobe renal cell carcinoma. Cancer Res. 2020;80:3830–40.
Google Scholar
Davis CF, Ricketts CJ, Wang M, Yang L, Cherniack AD, Shen H, et al. The somatic genomic landscape of chromophobe renal cell carcinoma. Cancer Cell. 2014;26:319–30.
Google Scholar
Yusenko MV, Kuiper RP, Boethe T, Ljungberg B, van Kessel AG, Kovacs G. High-resolution DNA copy number and gene expression analyses distinguish chromophobe renal cell carcinomas and renal oncocytomas. BMC Cancer. 2009;9:152.
Google Scholar
Pivovarcikova K, Alaghehbandan R, Vanecek T, Ohashi R, Pitra T, Hes O. TSC/mTOR pathway mutation associated eosinophilic/oncocytic renal neoplasms: a heterogeneous group of tumors with distinct morphology, immunohistochemical profile, and similar genetic background. Biomedicines. 2022;10:322.
Trpkov K, Williamson SR, Gill AJ, Adeniran AJ, Agaimy A, Alaghehbandan R, et al. Novel, emerging and provisional renal entities: the Genitourinary Pathology Society (GUPS) update on renal neoplasia. Mod Pathol. 2021;34:1167–84.
Google Scholar
Varela I, Tarpey P, Raine K, Huang D, Ong CK, Stephens P, et al. Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature. 2011;469:539–42.
Google Scholar
Peña-Llopis S, Vega-Rubín-de-Celis S, Liao A, Leng N, Pavía-Jiménez A, Wang S, et al. BAP1 loss defines a new class of renal cell carcinoma. Nat Genet. 2012;44:751–9.
Google Scholar
Dalgliesh GL, Furge K, Greenman C, Chen L, Bignell G, Butler A, et al. Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature. 2010;463:360–3.
Google Scholar
Jonasch E, Walker CL, Rathmell WK. Clear cell renal cell carcinoma ontogeny and mechanisms of lethality. Nat Rev Nephrol. 2021;17:245–61.
Google Scholar
Shen C, Kaelin WG Jr. The VHL/HIF axis in clear cell renal carcinoma. Semin Cancer Biol. 2013;23:18–25.
Google Scholar
Fay AP, de Velasco G, Ho TH, Van Allen EM, Murray B, Albiges L, et al. Whole-exome sequencing in two extreme phenotypes of response to VEGF-targeted therapies in patients with metastatic clear cell renal cell carcinoma. J Natl Compr Cancer Netw. 2016;14:820–4.
Google Scholar
Liu XD, Kong W, Peterson CB, McGrail DJ, Hoang A, Zhang X, et al. PBRM1 loss defines a nonimmunogenic tumor phenotype associated with checkpoint inhibitor resistance in renal carcinoma. Nat Commun. 2020;11:2135.
Google Scholar
Braun DA, Ishii Y, Walsh AM, Van Allen EM, Wu CJ, Shukla SA, et al. Clinical validation of PBRM1 alterations as a marker of immune checkpoint inhibitor response in renal cell carcinoma. JAMA Oncol. 2019;5:1631–3.
Google Scholar
Motzer RJ, Banchereau R, Hamidi H, Powles T, McDermott D, Atkins MB, et al. Molecular subsets in renal cancer determine outcome to checkpoint and angiogenesis blockade. Cancer Cell. 2020;38:803–17.e804.
Google Scholar
Li F, Mao G, Tong D, Huang J, Gu L, Yang W, et al. The histone mark H3K36me3 regulates human DNA mismatch repair through its interaction with MutSα. Cell. 2013;153:590–600.
Google Scholar
Castillo VF, Trpkov K, Saleeb R. Contemporary review of papillary renal cell carcinoma-current state and future directions. Virchows Arch. 2024;485:391–405.
Google Scholar
Alaghehbandan R, Przybycin CG, Verkarre V, Mehra R. Chromophobe renal cell carcinoma: novel molecular insights and clinicopathologic updates. Asian J Urol. 2022;9:1–11.
Google Scholar
Nickerson ML, Warren MB, Toro JR, Matrosova V, Glenn G, Turner ML, et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt-Hogg-Dubé syndrome. Cancer Cell. 2002;2:157–64.
Google Scholar
Zhang L, Henske EP. Chromophobe renal cell carcinoma: new genetic and metabolic insights. Urol Oncol. 2020;38:678–81.
Google Scholar
Dagher J, Brunot A, Evrard B, Kammerer-Jacquet SF, Beaumont M, Cornevin L, et al. Multiple metastatic clones assessed by an integrative multiomics strategy in clear cell renal carcinoma: a case study. J Clin Pathol. 2022;75:426–30.
Google Scholar
Schreiber RD, Old LJ, Smyth MJ. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science. 2011;331:1565–70.
Google Scholar
Bhargava P, Schnellmann RG. Mitochondrial energetics in the kidney. Nat Rev Nephrol. 2017;13:629–46.
Google Scholar
Wettersten HI, Aboud OA, Lara PN Jr, Weiss RH. Metabolic reprogramming in clear cell renal cell carcinoma. Nat Rev Nephrol. 2017;13:410–9.
Google Scholar
Wolf MM, Madden MZ, Arner EN, Bader JE, Ye X, Vlach L, et al. VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis. J Clin Invest. 2024;134:e173934.
Papandreou I, Cairns RA, Fontana L, Lim AL, Denko NC. HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption. Cell Metab. 2006;3:187–97.
Google Scholar
Kim JW, Tchernyshyov I, Semenza GL, Dang CV. HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia. Cell Metab. 2006;3:177–85.
Google Scholar
Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.
Zhang Y, Zhang S, Sun H, Xu L. The pathogenesis and therapeutic implications of metabolic reprogramming in renal cell carcinoma. Cell Death Discov. 2025;11:186.
Google Scholar
Qiu B, Ackerman D, Sanchez DJ, Li B, Ochocki JD, Grazioli A, et al. HIF2α-dependent lipid storage promotes endoplasmic reticulum homeostasis in clear-cell renal cell carcinoma. Cancer Discov. 2015;5:652–67.
Google Scholar
Yuan Y, Yang X, Li Y, Liu Q, Wu F, Qu H, et al. Expression and prognostic significance of fatty acid synthase in clear cell renal cell carcinoma. Pathol, Res Pract. 2020;216:153227.
Google Scholar
Hua X, Ge S, Zhang L, Jiang Q, Chen J, Xiao H, et al. MED15 is upregulated by HIF-2α and promotes proliferation and metastasis in clear cell renal cell carcinoma via activation of SREBP-dependent fatty acid synthesis. Cell Death Discov. 2024;10:188.
Google Scholar
Du W, Zhang L, Brett-Morris A, Aguila B, Kerner J, Hoppel CL, et al. HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism. Nat Commun. 2017;8:1769.
Google Scholar
Jarc E, Petan T. Lipid droplets and the management of cellular stress. Yale J Biol Med. 2019;92:435–52.
Google Scholar
Bozza PT, Bakker-Abreu I, Navarro-Xavier RA, Bandeira-Melo C. Lipid body function in eicosanoid synthesis: an update. Prostaglandins Leukot Essent Fatty Acids. 2011;85:205–13.
Google Scholar
Lacher SB, Dörr J, de Almeida GP, Hönninger J, Bayerl F, Hirschberger A, et al. PGE(2) limits effector expansion of tumour-infiltrating stem-like CD8(+) T cells. Nature. 2024;629:417–25.
Google Scholar
Gameiro PA, Yang J, Metelo AM, Pérez-Carro R, Baker R, Wang Z, et al. In vivo HIF-mediated reductive carboxylation is regulated by citrate levels and sensitizes VHL-deficient cells to glutamine deprivation. Cell Metab. 2013;17:372–85.
Google Scholar
Wettersten HI. Reprogramming of metabolism in kidney cancer. Semin Nephrol. 2020;40:2–13.
Google Scholar
DeBerardinis RJ, Cheng T. Q’s next: the diverse functions of glutamine in metabolism, cell biology and cancer. Oncogene. 2010;29:313–24.
Google Scholar
Semenza GL. Hypoxia-inducible factors in physiology and medicine. Cell. 2012;148:399–408.
Google Scholar
Shim EH, Livi CB, Rakheja D, Tan J, Benson D, Parekh V, et al. L-2-Hydroxyglutarate: an epigenetic modifier and putative oncometabolite in renal cancer. Cancer Discov. 2014;4:1290–8.
Google Scholar
Stone TW, Williams RO. Interactions of IDO and the kynurenine pathway with cell transduction systems and metabolism at the inflammation-cancer interface. Cancers. 2023;15:2895.
Brandacher G, Perathoner A, Ladurner R, Schneeberger S, Obrist P, Winkler C, et al. Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells. Clin Cancer Res. 2006;12:1144–51.
Google Scholar
Munn DH, Mellor AL. Indoleamine 2,3 dioxygenase and metabolic control of immune responses. Trends Immunol. 2013;34:137–43.
Google Scholar
Ohta A, Gorelik E, Prasad SJ, Ronchese F, Lukashev D, Wong MK, et al. A2A adenosine receptor protects tumors from antitumor T cells. Proc Natl Acad Sci USA. 2006;103:13132–7.
Google Scholar
Fischer K, Hoffmann P, Voelkl S, Meidenbauer N, Ammer J, Edinger M, et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood. 2007;109:3812–9.
Google Scholar
Husain Z, Huang Y, Seth P, Sukhatme VP. Tumor-derived lactate modifies antitumor immune response: effect on myeloid-derived suppressor cells and NK cells. J Immunol. 2013;191:1486–95.
Google Scholar
Cumberbatch MG, Rota M, Catto JW, La Vecchia C. The role of tobacco smoke in bladder and kidney carcinogenesis: a comparison of exposures and meta-analysis of incidence and mortality risks. Eur Urol. 2016;70:458–66.
Google Scholar
Hidayat K, Du X, Zou SY, Shi BM. Blood pressure and kidney cancer risk: meta-analysis of prospective studies. J Hypertens. 2017;35:1333–44.
Google Scholar
Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371:569–78.
Google Scholar
Hakimi AA, Reznik E, Lee CH, Creighton CJ, Brannon AR, Luna A, et al. An integrated metabolic atlas of clear cell renal cell carcinoma. Cancer Cell. 2016;29:104–16.
Google Scholar
Venkatesh N, Martini A, McQuade JL, Msaouel P, Hahn AW. Obesity and renal cell carcinoma: Biological mechanisms and perspectives. Semin Cancer Biol. 2023;94:21–33.
Google Scholar
Brauch H, Weirich G, Hornauer MA, Störkel S, Wöhl T, Brüning T. Trichloroethylene exposure and specific somatic mutations in patients with renal cell carcinoma. J Natl Cancer Inst. 1999;91:854–61.
Google Scholar
Brüning T, Pesch B, Wiesenhütter B, Rabstein S, Lammert M, Baumüller A, et al. Renal cell cancer risk and occupational exposure to trichloroethylene: results of a consecutive case-control study in Arnsberg, Germany. Am J Ind Med. 2003;43:274–85.
Google Scholar
Li J, Deng Z, Soerensen SJC, Kachuri L, Cardenas A, Graff RE, et al. Ambient air pollution and urological cancer risk: a systematic review and meta-analysis of epidemiological evidence. Nat Commun. 2024;15:5116.
Google Scholar
Hardie DG. AMPK-sensing energy while talking to other signaling pathways. Cell Metab. 2014;20:939–52.
Google Scholar
González A, Hall MN, Lin SC, Hardie DG. AMPK and TOR: the Yin and Yang of cellular nutrient sensing and growth control. Cell Metab. 2020;31:472–92.
Google Scholar
Kapur P, Brugarolas J, Trpkov K. Recent advances in renal tumors with TSC/mTOR Pathway abnormalities in patients with tuberous sclerosis complex and in the sporadic setting. Cancers. 2023;15:4043.
Massari F, Ciccarese C, Santoni M, Brunelli M, Piva F, Modena A, et al. Metabolic alterations in renal cell carcinoma. Cancer Treat Rev. 2015;41:767–76.
Google Scholar
Shackelford DB, Shaw RJ. The LKB1-AMPK pathway: metabolism and growth control in tumour suppression. Nat Rev Cancer. 2009;9:563–75.
Google Scholar
Gowans GJ, Hawley SA, Ross FA, Hardie DG. AMP is a true physiological regulator of AMP-activated protein kinase by both allosteric activation and enhancing net phosphorylation. Cell Metab. 2013;18:556–66.
Google Scholar
Shaw RJ, Kosmatka M, Bardeesy N, Hurley RL, Witters LA, DePinho RA, et al. The tumor suppressor LKB1 kinase directly activates AMP-activated kinase and regulates apoptosis in response to energy stress. Proc Natl Acad Sci USA. 2004;101:3329–35.
Google Scholar
Inoki K, Zhu T, Guan KL. TSC2 mediates cellular energy response to control cell growth and survival. Cell. 2003;115:577–90.
Google Scholar
Gwinn DM, Shackelford DB, Egan DF, Mihaylova MM, Mery A, Vasquez DS, et al. AMPK phosphorylation of raptor mediates a metabolic checkpoint. Mol cell. 2008;30:214–26.
Google Scholar
Yan M, Gingras MC, Dunlop EA, Nouët Y, Dupuy F, Jalali Z, et al. The tumor suppressor folliculin regulates AMPK-dependent metabolic transformation. J Clin Investig. 2014;124:2640–50.
Google Scholar
Maycotte P, Thorburn A. Autophagy and cancer therapy. Cancer Biol Ther. 2011;11:127–37.
Google Scholar
Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS, et al. Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res. 2012;72:1773–83.
Google Scholar
Saxton RA, Sabatini DM. mTOR signaling in growth, metabolism, and disease. Cell. 2017;168:960–76.
Google Scholar
Wolfson RL, Chantranupong L, Saxton RA, Shen K, Scaria SM, Cantor JR, et al. Sestrin2 is a leucine sensor for the mTORC1 pathway. Science. 2016;351:43–8.
Google Scholar
Sancak Y, Peterson TR, Shaul YD, Lindquist RA, Thoreen CC, Bar-Peled L, et al. The Rag GTPases bind raptor and mediate amino acid signaling to mTORC1. Science. 2008;320:1496–501.
Google Scholar
Kim E, Goraksha-Hicks P, Li L, Neufeld TP, Guan KL. Regulation of TORC1 by Rag GTPases in nutrient response. Nat Cell Biol. 2008;10:935–45.
Google Scholar
Menon S, Dibble CC, Talbott G, Hoxhaj G, Valvezan AJ, Takahashi H, et al. Spatial control of the TSC complex integrates insulin and nutrient regulation of mTORC1 at the lysosome. Cell. 2014;156:771–85.
Google Scholar
Yang H, Jiang X, Li B, Yang HJ, Miller M, Yang A, et al. Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40. Nature. 2017;552:368–73.
Google Scholar
Um SH, Frigerio F, Watanabe M, Picard F, Joaquin M, Sticker M, et al. Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity. Nature. 2004;431:200–5.
Google Scholar
O’Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, et al. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res. 2006;66:1500–8.
Google Scholar
Schmidt LS, Linehan WM. FLCN: the causative gene for Birt-Hogg-Dubé syndrome. Gene. 2018;640:28–42.
Google Scholar
Gupta S, Dasari S, Warren RR, Shen W, Urban RM, Stanton ML, et al. Renal Neoplasia in Birt-Hogg-Dubé syndrome: integrated histopathologic, bulk, and single-cell transcriptomic analysis. Eur Urol. 2025;88:263–73.
Google Scholar
Schmidt LS, Linehan WM. Molecular genetics and clinical features of Birt-Hogg-Dubé syndrome. Nat Rev Urol. 2015;12:558–69.
Google Scholar
Meng J, Ferguson SM. GATOR1-dependent recruitment of FLCN-FNIP to lysosomes coordinates Rag GTPase heterodimer nucleotide status in response to amino acids. J Cell Biol. 2018;217:2765–76.
Google Scholar
Tsun ZY, Bar-Peled L, Chantranupong L, Zoncu R, Wang T, Kim C, et al. The folliculin tumor suppressor is a GAP for the RagC/D GTPases that signal amino acid levels to mTORC1. Mol Cell. 2013;52:495–505.
Google Scholar
Lawrence RE, Fromm SA, Fu Y, Yokom AL, Kim DJ, Thelen AM, et al. Structural mechanism of a Rag GTPase activation checkpoint by the lysosomal folliculin complex. Science. 2019;366:971–7.
Google Scholar
Napolitano G, Di Malta C, Esposito A, de Araujo MEG, Pece S, Bertalot G, et al. A substrate-specific mTORC1 pathway underlies Birt-Hogg-Dubé syndrome. Nature. 2020;585:597–602.
Google Scholar
Sambri I, Ferniani M, Ballabio A. Ragopathies and the rising influence of RagGTPases on human diseases. Nat Commun. 2024;15:5812.
Google Scholar
Puertollano R. mTOR and lysosome regulation. F1000prime Rep. 2014;6:52.
Google Scholar
Hasumi H, Baba M, Hasumi Y, Huang Y, Oh H, Hughes RM, et al. Regulation of mitochondrial oxidative metabolism by tumor suppressor FLCN. J Natl Cancer Inst. 2012;104:1750–64.
Google Scholar
Nezami BG, Teh BT, Lin X, Yang XJ. Molecular pathogenesis of renal neoplasms in patients with Birt–Hogg–Dubé syndrome. J Mol Pathol. 2024;5:478–96.
Google Scholar
Goodwin, Walkup JM, WGt, Hooper K, Li T, Kishi-Itakura C, et al. GABARAP sequesters the FLCN-FNIP tumor suppressor complex to couple autophagy with lysosomal biogenesis. Sci Adv. 2021;7:eabj2485.
Google Scholar
Trpkov K, Abou-Ouf H, Hes O, Lopez JI, Nesi G, Comperat E, et al. Eosinophilic solid and cystic renal cell carcinoma (ESC RCC): further morphologic and molecular characterization of ESC RCC as a distinct entity. Am J Surg Pathol. 2017;41:1299–308.
Google Scholar
Inoki K, Li Y, Xu T, Guan KL. Rheb GTPase is a direct target of TSC2 GAP activity and regulates mTOR signaling. Genes Dev. 2003;17:1829–34.
Google Scholar
Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature. 2007;450:736–40.
Google Scholar
Ma XM, Blenis J. Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol. 2009;10:307–18.
Google Scholar
Bakouny Z, Sadagopan A, Ravi P, Metaferia NY, Li J, AbuHammad S, et al. Integrative clinical and molecular characterization of translocation renal cell carcinoma. Cell Rep. 2022;38:110190.
Google Scholar
Qu Y, Wu X, Anwaier A, Feng J, Xu W, Pei X, et al. Proteogenomic characterization of MiT family translocation renal cell carcinoma. Nat Commun. 2022;13:7494.
Google Scholar
Kauffman EC, Ricketts CJ, Rais-Bahrami S, Yang Y, Merino MJ, Bottaro DP, et al. Molecular genetics and cellular features of TFE3 and TFEB fusion kidney cancers. Nat Rev Urol. 2014;11:465–75.
Google Scholar
Li J, Huang K, Thakur M, McBride F, Sadagopan A, Gallant DS, et al. Oncogenic TFE3 fusions drive OXPHOS and confer metabolic vulnerabilities in translocation renal cell carcinoma. Nat Metab. 2025;7:478–92.
Google Scholar
Ged Y, Feinaj A, Baraban E, Singla N. Management of translocation carcinomas of the kidney. Transl Cancer Res. 2024;13:6438–47.
Google Scholar
Linehan WM, Ricketts CJ. The metabolic basis of kidney cancer. Semin Cancer Biol. 2013;23:46–55.
Google Scholar
Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, et al. HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell. 2005;8:143–53.
Google Scholar
Linehan WM, Schmidt LS, Crooks DR, Wei D, Srinivasan R, Lang M, et al. The metabolic basis of kidney cancer. Cancer Discov. 2019;9:1006–21.
Google Scholar
Ooi A, Wong JC, Petillo D, Roossien D, Perrier-Trudova V, Whitten D, et al. An antioxidant response phenotype shared between hereditary and sporadic type 2 papillary renal cell carcinoma. Cancer Cell. 2011;20:511–23.
Google Scholar
Sudarshan S, Sourbier C, Kong HS, Block K, Valera Romero VA, Yang Y, et al. Fumarate hydratase deficiency in renal cancer induces glycolytic addiction and hypoxia-inducible transcription factor 1alpha stabilization by glucose-dependent generation of reactive oxygen species. Mol Cell Biol. 2009;29:4080–90.
Google Scholar
Fei C, Zhen X, Shiqiang Z, Jun P. Frontier knowledge and future directions of programmed cell death in clear cell renal cell carcinoma. Cell Death Discov. 2024;10:113.
Google Scholar
Tong Y, Kai J, Wang S, Yu Y, Xie S, Zheng H, et al. VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1α/HO-1 pathway. Cell Death Dis. 2021;12:621.
Google Scholar
Mazumder S, Higgins PJ, Samarakoon R. Downstream targets of VHL/HIF-α signaling in renal clear cell carcinoma progression: mechanisms and therapeutic relevance. Cancers. 2023;15:1316.
Bakouny Z, Braun DA, Shukla SA, Pan W, Gao X, Hou Y, et al. Integrative molecular characterization of sarcomatoid and rhabdoid renal cell carcinoma. Nat Commun. 2021;12:808.
Google Scholar
Bihr S, Ohashi R, Moore AL, Rüschoff JH, Beisel C, Hermanns T, et al. Expression and mutation patterns of PBRM1, BAP1 and SETD2 mirror specific evolutionary subtypes in clear cell renal cell carcinoma. Neoplasia. 2019;21:247–56.
Google Scholar
Rini BI, Signoretti S, Choueiri TK, McDermott DF, Motzer RJ, George S, et al. Long-term outcomes with nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. J Immunother Cancer. 2022;10:e005445.
Hahn AW, Surasi DS, Viscuse PV, Bathala TK, Wiele AJ, Campbell MT, et al. Treatment outcomes in patients with metastatic renal cell carcinoma with sarcomatoid and/or rhabdoid dedifferentiation after progression on immune checkpoint therapy. Oncologist. 2024;29:392–9.
Google Scholar
Kaelin WG Jr. The von Hippel-Lindau tumor suppressor protein and clear cell renal carcinoma. Clin Cancer Res. 2007;13:680s–4s.
Google Scholar
Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.
Google Scholar
Miess H, Dankworth B, Gouw AM, Rosenfeldt M, Schmitz W, Jiang M, et al. The glutathione redox system is essential to prevent ferroptosis caused by impaired lipid metabolism in clear cell renal cell carcinoma. Oncogene. 2018;37:5435–50.
Google Scholar
Zou Y, Palte MJ, Deik AA, Li H, Eaton JK, Wang W, et al. A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis. Nat Commun. 2019;10:1617.
Google Scholar
Haas NB, Appleman LJ, Stein M, Redlinger M, Wilks M, Xu X, et al. Autophagy inhibition to augment mTOR inhibition: a phase I/II trial of everolimus and hydroxychloroquine in patients with previously treated renal cell carcinoma. Clin Cancer Res. 2019;25:2080–7.
Google Scholar
Sato Y, Yoshizato T, Shiraishi Y, Maekawa S, Okuno Y, Kamura T, et al. Integrated molecular analysis of clear-cell renal cell carcinoma. Nat Genet. 2013;45:860–7.
Google Scholar
Rini BI, Motzer RJ, Powles T, McDermott DF, Escudier B, Donskov F, et al. Atezolizumab plus bevacizumab versus sunitinib for patients with untreated metastatic renal cell carcinoma and sarcomatoid features: a prespecified subgroup analysis of the IMmotion151 clinical trial. Eur Urol. 2021;79:659–62.
Google Scholar
Delahunt B, Cheville JC, Martignoni G, Humphrey PA, Magi-Galluzzi C, McKenney J, et al. The International Society of Urological Pathology (ISUP) grading system for renal cell carcinoma and other prognostic parameters. Am J Surg Pathol. 2013;37:1490–504.
Google Scholar
de Peralta-Venturina M, Moch H, Amin M, Tamboli P, Hailemariam S, Mihatsch M, et al. Sarcomatoid differentiation in renal cell carcinoma: a study of 101 cases. Am J Surg Pathol. 2001;25:275–84.
Google Scholar
Malouf GG, Ali SM, Wang K, Balasubramanian S, Ross JS, Miller VA, et al. Genomic characterization of renal cell carcinoma with sarcomatoid dedifferentiation pinpoints recurrent genomic alterations. Eur Urol. 2016;70:348–57.
Google Scholar
Carretero-González A, Lora D, Martín Sobrino I, Sáez Sanz I, Bourlon MT, Anido Herranz U, et al. The value of PD-L1 expression as predictive biomarker in metastatic renal cell carcinoma patients: a meta-analysis of randomized clinical trials. Cancers. 2020;12:1945.
Tannir NM, Signoretti S, Choueiri TK, McDermott DF, Motzer RJ, Flaifel A, et al. Efficacy and safety of nivolumab plus ipilimumab versus sunitinib in first-line treatment of patients with advanced sarcomatoid renal cell carcinoma. Clin Cancer Res. 2021;27:78–86.
Google Scholar
Bi M, Zhao S, Said JW, Merino MJ, Adeniran AJ, Xie Z, et al. Genomic characterization of sarcomatoid transformation in clear cell renal cell carcinoma. Proc Natl Acad Sci USA. 2016;113:2170–5.
Google Scholar
Motzer RJ, Jonasch E, Boyle S, Carlo MI, Manley B, Agarwal N, et al. NCCN guidelines insights: kidney cancer, version 1.2021. J Natl Compr Cancer Netw. 2020;18:1160–70.
Fyfe G, Fisher RI, Rosenberg SA, Sznol M, Parkinson DR, Louie AC. Results of treatment of 255 patients with metastatic renal cell carcinoma who received high-dose recombinant interleukin-2 therapy. J Clin Oncol. 1995;13:688–96.
Google Scholar
Rosenberg SA, Lotze MT, Muul LM, Leitman S, Chang AE, Ettinghausen SE, et al. Observations on the systemic administration of autologous lymphokine-activated killer cells and recombinant interleukin-2 to patients with metastatic cancer. N Engl J Med. 1985;313:1485–92.
Google Scholar
Klapper JA, Downey SG, Smith FO, Yang JC, Hughes MS, Kammula US, et al. High-dose interleukin-2 for the treatment of metastatic renal cell carcinoma: a retrospective analysis of response and survival in patients treated in the surgery branch at the National Cancer Institute between 1986 and 2006. Cancer. 2008;113:293–301.
Google Scholar
McDermott DF, Regan MM, Clark JI, Flaherty LE, Weiss GR, Logan TF, et al. Randomized phase III trial of high-dose interleukin-2 versus subcutaneous interleukin-2 and interferon in patients with metastatic renal cell carcinoma. J Clin Oncol. 2005;23:133–41.
Google Scholar
Kaelin WG Jr. Molecular basis of the VHL hereditary cancer syndrome. Nat Rev Cancer. 2002;2:673–82.
Google Scholar
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356:125–34.
Google Scholar
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Rixe O, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115–24.
Google Scholar
Pick AM, Nystrom KK. Pazopanib for the treatment of metastatic renal cell carcinoma. Clin Ther. 2012;34:511–20.
Google Scholar
Gupta S, Spiess PE. The prospects of pazopanib in advanced renal cell carcinoma. Ther Adv Urol. 2013;5:223–32.
Google Scholar
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med. 2013;369:722–31.
Google Scholar
Sonpavde G, Hutson TE, Rini BI. Axitinib for renal cell carcinoma. Expert Opin Investig Drugs. 2008;17:741–8.
Google Scholar
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931–9.
Google Scholar
Rini BI, Plimack ER, Stus V, Gafanov R, Hawkins R, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1116–27.
Google Scholar
Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1814–23.
Google Scholar
Yakes FM, Chen J, Tan J, Yamaguchi K, Shi Y, Yu P, et al. Cabozantinib (XL184), a novel MET and VEGFR2 inhibitor, simultaneously suppresses metastasis, angiogenesis, and tumor growth. Mol Cancer Ther. 2011;10:2298–308.
Google Scholar
Motzer RJ, Hutson TE, Glen H, Michaelson MD, Molina A, Eisen T, et al. Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. Lancet Oncol. 2015;16:1473–82.
Google Scholar
Rini BI, Pal SK, Escudier BJ, Atkins MB, Hutson TE, Porta C, et al. Tivozanib versus sorafenib in patients with advanced renal cell carcinoma (TIVO-3): a phase 3, multicentre, randomised, controlled, open-label study. Lancet Oncol. 2020;21:95–104.
Google Scholar
Hsu J, Chong C, Serrill J, Goon L, Balayan J, Johnson EN, et al. Preclinical characterization of XL092, a novel receptor tyrosine kinase inhibitor of MET, VEGFR2, AXL, and MER. Mol Cancer Ther. 2023;22:179–91.
Google Scholar
Pal SK, Powles T, Kanesvaran R, Molina-Cerrillo J, Feldman DR, Barata P, et al. STELLAR-304: a phase III study of zanzalintinib (XL092) plus nivolumab in advanced non-clear cell renal cell carcinoma. Future Oncol. 2025;21:787–94.
Google Scholar
Miricescu D, Balan DG, Tulin A, Stiru O, Vacaroiu IA, Mihai DA, et al. PI3K/AKT/mTOR signalling pathway involvement in renal cell carcinoma pathogenesis (Review). Exp Ther Med. 2021;21:540.
Google Scholar
Hudes G, Carducci M, Tomczak P, Dutcher J, Figlin R, Kapoor A, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271–81.
Google Scholar
Agarwala SS, Case S. Everolimus (RAD001) in the treatment of advanced renal cell carcinoma: a review. Oncologist. 2010;15:236–45.
Google Scholar
Motzer RJ, Escudier B, McDermott DF, George S, Hammers HJ, Srinivas S, et al. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373:1803–13.
Google Scholar
Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Chang YH, et al. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385:683–94.
Google Scholar
Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12:252–64.
Google Scholar
Xu JX, Maher VE, Zhang L, Tang S, Sridhara R, Ibrahim A, et al. FDA approval summary: nivolumab in advanced renal cell carcinoma after anti-angiogenic therapy and exploratory predictive biomarker analysis. oncologist. 2017;22:311–7.
Google Scholar
Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 2018;8:1069–86.
Google Scholar
Motzer RJ, Tannir NM, McDermott DF, Arén Frontera O, Melichar B, Choueiri TK, et al. Nivolumab plus ipilimumab versus sunitinib in advanced renal-cell carcinoma. N Engl J Med. 2018;378:1277–90.
Google Scholar
Tannir NM, Albigès L, McDermott DF, Burotto M, Choueiri TK, Hammers HJ, et al. Nivolumab plus ipilimumab versus sunitinib for first-line treatment of advanced renal cell carcinoma: extended 8-year follow-up results of efficacy and safety from the phase III CheckMate 214 trial. Ann Oncol. 2024;35:1026–38.
Google Scholar
Motzer RJ, Penkov K, Haanen J, Rini B, Albiges L, Campbell MT, et al. Avelumab plus axitinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2019;380:1103–15.
Google Scholar
Choueiri TK, Powles T, Burotto M, Escudier B, Bourlon MT, Zurawski B, et al. Nivolumab plus cabozantinib versus sunitinib for advanced renal-cell carcinoma. N Engl J Med. 2021;384:829–41.
Google Scholar
Rini BI, Plimack ER, Stus V, Gafanov R, Waddell T, Nosov D, et al. Pembrolizumab plus axitinib versus sunitinib for advanced clear cell renal cell carcinoma: 5-year survival and biomarker analyses of the phase 3 KEYNOTE-426 trial. Nat Med. 2025;31:3475–84.
Google Scholar
Motzer RJ, Escudier B, Burotto M, Powles T, Apolo AB, Bourlon MT, et al. Final analysis of nivolumab plus cabozantinib for advanced renal cell carcinoma from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2026;37:33–43.
Google Scholar
Motzer RJ, Porta C, Eto M, Powles T, Grünwald V, Hutson TE, et al. Lenvatinib plus pembrolizumab versus sunitinib in first-line treatment of advanced renal cell carcinoma: final prespecified overall survival analysis of CLEAR, a phase III study. J Clin Oncol. 2024;42:1222–8.
Google Scholar
Powles T, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for clear cell renal cell carcinoma (KEYNOTE-564): 30-month follow-up analysis of a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2022;23:1133–44.
Google Scholar
Choueiri TK, Tomczak P, Park SH, Venugopal B, Ferguson T, Symeonides SN, et al. Overall survival with adjuvant pembrolizumab in renal-cell carcinoma. N Engl J Med. 2024;390:1359–71.
Google Scholar
Ahmed R, Ornstein MC. Targeting HIF-2 alpha in renal cell carcinoma. Curr Treat options Oncol. 2023;24:1183–98.
Google Scholar
Cuvillier O. The therapeutic potential of HIF-2 antagonism in renal cell carcinoma. Transl Androl Urol. 2017;6:131–3.
Google Scholar
Ren X, Diao X, Zhuang J, Wu D. Structural basis for the allosteric inhibition of hypoxia-inducible factor (HIF)-2 by belzutifan. Mol Pharmacol. 2022;102:240–247.
Dogra R, Vaishampayan U. Hypoxia inducible factor-2α (HIF-2α) pathway inhibitors. J Kidney Cancer VHL. 2025;12:1–15.
Google Scholar
Natarajan V, Satalkar V, Gumbart JC, Torres M. Molecular dynamics reveals altered interactions between belzutifan and HIF-2 with natural variant G323E or proximal phosphorylation at T324. ACS Omega. 2024;9:37843–55.
Google Scholar
Bindra RS, Vasselli JR, Stearman R, Linehan WM, Klausner RD. VHL-mediated hypoxia regulation of cyclin D1 in renal carcinoma cells. Cancer Res. 2002;62:3014–9.
Google Scholar
Fallah J, Heiss BL, Joeng HK, Weinstock C, Gao X, Pierce WF, et al. FDA approval summary: belzutifan for patients with advanced renal cell carcinoma. Clin Cancer Res. 2024;30:5003–8.
Google Scholar
Jonasch E, Donskov F, Iliopoulos O, Rathmell WK, Narayan VK, Maughan BL, et al. Belzutifan for renal cell carcinoma in von Hippel-Lindau disease. N Engl J Med. 2021;385:2036–46.
Google Scholar
Fallah J, Brave MH, Weinstock C, Mehta GU, Bradford D, Gittleman H, et al. FDA approval summary: belzutifan for von Hippel-Lindau disease-associated tumors. Clin Cancer Res. 2022;28:4843–8.
Google Scholar
Ghasemi M, Kim JY, Seitz L, Jin L, Foster PG, Liao KH, et al. Pharmacokinetics, pharmacodynamics and safety of casdatifan, a novel hypoxia-inducible factor-2α inhibitor, in healthy participants. Br J Clin Pharmacol. 2025;91:3366–77.
Google Scholar
Fukumura D, Kloepper J, Amoozgar Z, Duda DG, Jain RK. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol. 2018;15:325–40.
Google Scholar
Wallin JJ, Bendell JC, Funke R, Sznol M, Korski K, Jones S, et al. Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma. Nat Commun. 2016;7:12624.
Google Scholar
Fang W, Zhao Y, Luo Y, Yang R, Huang Y, He Z, et al. Ivonescimab plus chemotherapy in non-small cell lung cancer with EGFR Variant: a randomized clinical trial. JAMA. 2024;332:561–70.
Google Scholar
Labrijn AF, Janmaat ML, Reichert JM, Parren P. Bispecific antibodies: a mechanistic review of the pipeline. Nat Rev Drug Discov. 2019;18:585–608.
Google Scholar
Rini BI, Battle D, Figlin RA, George DJ, Hammers H, Hutson T, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of advanced renal cell carcinoma (RCC). J Immunother Cancer. 2019;7:354.
Google Scholar
Spranger S, Bao R, Gajewski TF. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature. 2015;523:231–5.
Google Scholar
Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations ASSOCIATED WITH ACQUIRED RESIStance to PD-1 BLOCKADE IN Melanoma. N Engl J Med. 2016;375:819–29.
Google Scholar
Sharma P, Hu-Lieskovan S, Wargo JA, Ribas A. Primary, ADAPTIVE, AND ACQUIRED RESISTANCE TO CANCER IMMunotherapy. Cell. 2017;168:707–23.
Google Scholar
Pal SK, Tran B, Haanen J, Hurwitz ME, Sacher A, Tannir NM, et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. 2024;14:1176–89.
Google Scholar
Bohac C, Pal S, Sweis R, Kotecha R, Runcie K, Bilen M, et al. 17: A Phase 1, multiple-dose study to evaluate the safety and tolerability of first-in-class XmAb819 (ENPP3 x CD3) in subjects with relapsed or refractory clear cell renal cell carcinoma (ccRCC) (NCT05433). Oncologist. 2025;30:oyaf276.018.
Zarrabi K, Walzer E, Zibelman M. Immune checkpoint inhibition in advanced non-clear cell renal cell carcinoma: leveraging success from clear cell histology into new opportunities. Cancers. 2021;13:3652.
Pal SK, Tangen C, Thompson IM Jr, Balzer-Haas N, George DJ, Heng DYC, et al. A comparison of sunitinib with cabozantinib, crizotinib, and savolitinib for treatment of advanced papillary renal cell carcinoma: a randomised, open-label, phase 2 trial. Lancet. 2021;397:695–703.
Google Scholar
Choueiri TK, Plimack E, Arkenau HT, Jonasch E, Heng DYC, Powles T, et al. Biomarker-based phase II trial of savolitinib in patients with advanced papillary renal cell cancer. J Clin Oncol. 2017;35:2993–3001.
Google Scholar
Henske EP, Cheng L, Hakimi AA, Choueiri TK, Braun DA. Chromophobe renal cell carcinoma. Cancer Cell. 2023;41:1383–8.
Google Scholar
Hutson TE, Michaelson MD, Kuzel TM, Agarwal N, Molina AM, Hsieh JJ, et al. A single-arm, multicenter, phase 2 study of lenvatinib plus everolimus in patients with advanced non-clear cell renal cell carcinoma. Eur Urol. 2021;80:162–70.
Google Scholar
Su Y, Hong AL. Recent advances in renal medullary carcinoma. Int J Mol Sci. 2022;23:7097.
Whaley RD, Msaouel P, Cheville JC, Gupta S. Renal medullary carcinoma: a contemporary update. Kidney Cancer. 2025;9:50–60.
Msaouel P, Tannir NM, Walker CL. A model linking sickle cell hemoglobinopathies and SMARCB1 Loss In Renal Medullary Carcinoma. Clin Cancer Res. 2018;24:2044–9.
Google Scholar
Weston W, Sit C, Dafydd DA, Kelly-Morland C, Sohaib A, Adamane S, et al. Renal medullary carcinoma: a systematic review of clinical and radiological findings. Int Urol Nephrol. 2026;58:3407–3418.
Davis CJ Jr, Mostofi FK, Sesterhenn IA. Renal medullary carcinoma. The seventh sickle cell nephropathy. Am J Surg Pathol. 1995;19:1–11.
Google Scholar
Hong AL, Tseng YY, Wala JA, Kim WJ, Kynnap BD, Doshi MB, et al. Renal medullary carcinomas depend upon SMARCB1 loss and are sensitive to proteasome inhibition. eLife. 2019;8:e44161.
Valcarcel-Jimenez L, Frezza C. Fumarate hydratase (FH) and cancer: a paradigm of oncometabolism. Br J Cancer. 2023;129:1546–57.
Google Scholar
Sourbier C, Ricketts CJ, Matsumoto S, Crooks DR, Liao PJ, Mannes PZ, et al. Targeting ABL1-mediated oxidative stress adaptation in fumarate hydratase-deficient cancer. Cancer Cell. 2014;26:840–50.
Google Scholar
Zhang C, Li L, Zhang Y, Zeng C. Hereditary leiomyomatosis and renal cell cancer: recent insights into mechanisms and systemic treatment. Front Oncol. 2021;11:686556.
Google Scholar
Lindner AK, Tulchiner G, Seeber A, Siska PJ, Thurnher M, Pichler R. Targeting strategies in the treatment of fumarate hydratase deficient renal cell carcinoma. Front Oncol. 2022;12:906014.
Google Scholar
Srinivasan R, Gurram S, Singer EA, Sidana A, Al Harthy M, Ball MW, et al. Bevacizumab and erlotinib in hereditary and sporadic papillary kidney cancer. N Engl J Med. 2025;392:2346–56.
Google Scholar
El-Mokadem I, Fitzpatrick J, Bondad J, Rauchhaus P, Cunningham J, Pratt N, et al. Chromosome 9p deletion in clear cell renal cell carcinoma predicts recurrence and survival following surgery. Br J Cancer. 2014;111:1381–90.
Google Scholar
McGregor BA, Xie W, Berg SA, Xu W, Viswanathan SR, McDermott D, et al. CDK4/6 inhibition with abemaciclib in patients with previously treated advanced renal cell carcinoma. Clin Genitourin Cancer. 2025;23:102318.
Google Scholar
Vasan K, Werner M, Chandel NS. Mitochondrial metabolism as a target for cancer therapy. Cell Metab. 2020;32:341–52.
Google Scholar
Pan X, Cracan V. Translocation renal cell carcinoma says no to the Warburg effect. Nat Metab. 2025;7:438–40.
Google Scholar
Arner EN, Rathmell JC. Metabolic programming and immune suppression in the tumor microenvironment. Cancer Cell. 2023;41:421–33.
Google Scholar
Al-Zoubi RM, Elaarag M, Al-Qudimat AR, Al-Hurani EA, Fares ZE, Farhan A, et al. IDO and TDO inhibitors in cancer immunotherapy: mechanisms, clinical development, and future directions. Front Pharmacol. 2025;16:1632446.
Google Scholar
Dizman N, Meza L, Bergerot P, Alcantara M, Dorff T, Lyou Y, et al. Nivolumab plus ipilimumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2022;28:704–12.
Google Scholar
Ebrahimi H, Dizman N, Meza L, Malhotra J, Li X, Dorff T, et al. Cabozantinib and nivolumab with or without live bacterial supplementation in metastatic renal cell carcinoma: a randomized phase 1 trial. Nat Med. 2024;30:2576–85.
Google Scholar
Yarchoan M, Powderly JD, Bastos BR, Karasic TB, Crysler OV, Munster PN, et al. First-in-human phase I trial of TPST-1120, an inhibitor of PPARα, as monotherapy or in combination with nivolumab, in patients with advanced solid tumors. Cancer Res Commun. 2024;4:1100–10.
Google Scholar
Hakimi AA, Ostrovnaya I, Reva B, Schultz N, Chen YB, Gonen M, et al. Adverse outcomes in clear cell renal cell carcinoma with mutations of 3p21 epigenetic regulators BAP1 and SETD2: a report by MSKCC and the KIRC TCGA research network. Clin Cancer Res. 2013;19:3259–67.
Google Scholar
Sun C, Zhao C, Li S, Wang J, Zhou Q, Sun J, et al. EZH2 Expression is increased in BAP1-mutant renal clear cell carcinoma and is related to poor prognosis. J Cancer. 2018;9:3787–96.
Google Scholar
LaFave LM, Béguelin W, Koche R, Teater M, Spitzer B, Chramiec A, et al. Loss of BAP1 function leads to EZH2-dependent transformation. Nat Med. 2015;21:1344–9.
Google Scholar
Fischer C, Leithner K, Wohlkoenig C, Quehenberger F, Bertsch A, Olschewski A, et al. Panobinostat reduces hypoxia-induced cisplatin resistance of non-small cell lung carcinoma cells via HIF-1α destabilization. Mol Cancer. 2015;14:4.
Google Scholar
Hainsworth JD, Infante JR, Spigel DR, Arrowsmith ER, Boccia RV, Burris HA. A phase II trial of panobinostat, a histone deacetylase inhibitor, in the treatment of patients with refractory metastatic renal cell carcinoma. Cancer Invest. 2011;29:451–5.
Google Scholar
Tannir NM, Agarwal N, Porta C, Lawrence NJ, Motzer R, McGregor B, et al. Efficacy and safety of telaglenastat plus cabozantinib vs placebo plus cabozantinib in patients with advanced renal cell carcinoma: the CANTATA randomized clinical trial. JAMA Oncol. 2022;8:1411–8.
Google Scholar
Finicle BT, Jayashankar V, Edinger AL. Nutrient scavenging in cancer. Nat Rev Cancer. 2018;18:619–33.
Google Scholar
Gantner BN, Palma FR, Pandkar MR, Sakiyama MJ, Arango D, DeNicola GM, et al. Metabolism and epigenetics: drivers of tumor cell plasticity and treatment outcomes. Trends Cancer. 2024;10:992–1008.
Google Scholar
Izzo LT, Affronti HC, Wellen KE. The bidirectional relationship between cancer epigenetics and metabolism. Annu Rev Cancer Biol. 2021;5:235–57.
Google Scholar
McDermott DF, Huseni MA, Atkins MB, Motzer RJ, Rini BI, Escudier B, et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat Med. 2018;24:749–57.
Google Scholar
Rini BI, Powles T, Atkins MB, Escudier B, McDermott DF, Suarez C, et al. Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial. Lancet. 2019;393:2404–15.
Google Scholar
Motzer RJ, Powles T, Atkins MB, Escudier B, McDermott DF, Alekseev BY, et al. Final overall survival and molecular analysis in IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab vs sunitinib in patients with previously untreated metastatic renal cell carcinoma. JAMA Oncol. 2022;8:275–80.
Google Scholar
Choueiri TK, Donahue AC, Braun DA, Rini BI, Powles T, Haanen J, et al. Integrative analyses of tumor and peripheral biomarkers in the treatment of advanced renal cell carcinoma. Cancer Discov. 2024;14:406–23.
Google Scholar
Motzer RJ, Robbins PB, Powles T, Albiges L, Haanen JB, Larkin J, et al. Avelumab plus axitinib versus sunitinib in advanced renal cell carcinoma: biomarker analysis of the phase 3 JAVELIN Renal 101 trial. Nat Med. 2020;26:1733–41.
Google Scholar
Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH. Tertiary lymphoid structures in the era of cancer immunotherapy. Nat Rev Cancer. 2019;19:307–25.
Google Scholar
Meylan M, Petitprez F, Becht E, Bougoüin A, Pupier G, Calvez A, et al. Tertiary lymphoid structures generate and propagate anti-tumor antibody-producing plasma cells in renal cell cancer. Immunity. 2022;55:527–41.e525.
Google Scholar
Hugaboom MB, Wirth LV, Street K, Ruthen N, Jegede OA, Schindler NR, et al. Presence of tertiary lymphoid structures and exhausted tissue-resident T cells determines clinical response to PD-1 blockade in renal cell carcinoma. Cancer Discov. 2025;15:948–68.
Google Scholar
Koh Y, Kato T, Yamamichi G, Tomiyama E, Matsushita M, Hatano K, et al. Evaluation of the diagnostic concordance of FDA-approved PD-L1 assays in clear cell renal cell carcinoma. Sci Rep. 2025;15:21253.
Google Scholar
Ko JJ, Xie W, Kroeger N, Lee JL, Rini BI, Knox JJ, et al. The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study. Lancet Oncol. 2015;16:293–300.
Google Scholar
Mantia CM, McDermott DF. Vascular endothelial growth factor and programmed death-1 pathway inhibitors in renal cell carcinoma. Cancer. 2019;125:4148–57.
Google Scholar
Kapur P, Rajaram S, Brugarolas J. The expanding role of BAP1 in clear cell renal cell carcinoma. Hum Pathol. 2023;133:22–31.
Google Scholar
Hwang JK, Agarwal N, Brugarolas J, Zhang T. Checking the Hippo in Sarcomatoid Renal Cell Carcinoma with Immunotherapy. Clin Cancer Res. 2021;27:5–7.
Google Scholar
Gopalakrishnan V, Spencer CN, Nezi L, Reuben A, Andrews MC, Karpinets TV, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018;359:97–103.
Google Scholar
Routy B, Le Chatelier E, Derosa L, Duong CPM, Alou MT, Daillère R, et al. Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors. Science. 2018;359:91–7.
Google Scholar
Ciccarese C, Porcari S, Buti S, Fornarini G, Primi F, Giudice GC, et al. LBA77 Fecal microbiota transplantation (FMT) versus placebo in patients receiving pembrolizumab plus axitinib for metastatic renal cell carcinoma: preliminary results of the randomized phase II TACITO trial. Ann Oncol. 2024;35:S1264.
McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–9.
Google Scholar
McKay RR, Bossé D, Choueiri TK. Evolving systemic treatment landscape for patients with advanced renal cell carcinoma. J Clin Oncol. 2018;36:3615–3623.

