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Although immune checkpoint inhibitors and vascular endothelial growth factor-targeted therapies have improved outcomes, resistance remains common due to adaptive network plasticity. Selected natural products have been reported to exhibit multitarget regulatory activities that may influence interconnected oncogenic pathways. This review highlights how compounds such as curcumin, resveratrol, quercetin, and epigallocatechin-3-gallate modulate the VHL-HIF axis, disrupt metabolic and redox homeostasis, and influence tumor\u2013immune system interactions in ccRCC. We propose a system-level framework in which natural products enhance therapeutic sensitivity; however, further validation is required for clinical translation.<\/jats:p>","DOI":"10.3390\/ijms27104584","type":"journal-article","created":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T12:30:51Z","timestamp":1779280251000},"page":"4584","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Natural Products in Clear Cell Renal Cell Carcinoma: Rewiring the VHL-HIF Axis, Metabolic Plasticity, and Tumor\u2013Immune Interactions"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2833-5609","authenticated-orcid":false,"given":"Yao-Chou","family":"Tsai","sequence":"first","affiliation":[{"name":"Division of Urology, Department of Surgery, Taipei Tzuchi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"},{"name":"School of Medicine, Buddhist Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-9645-0609","authenticated-orcid":false,"given":"Chung-Che","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Nursing, Cardinal Tien College of Healthcare and Management, New Taipei City 231038, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8274-2344","authenticated-orcid":false,"given":"Vincent F. S.","family":"Tsai","sequence":"additional","affiliation":[{"name":"Division of Urology, Department of Surgery, Taipei Tzuchi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei City 23142, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Hung","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Cathay General Hospital, Taipei 106438, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5702-5730","authenticated-orcid":false,"given":"Chan-Yen","family":"Kuo","sequence":"additional","affiliation":[{"name":"Institute of Oral Medicine and Materials, College of Medicine, Tzu Chi University, Hualien 97004, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Qi, X., Li, Q., Che, X., Wang, Q., and Wu, G. (2021). The Uniqueness of Clear Cell Renal Cell Carcinoma: Summary of the Process and Abnormality of Glucose Metabolism and Lipid Metabolism in ccRCC. Front. Oncol., 11.","DOI":"10.3389\/fonc.2021.727778"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s12929-024-01111-9","article-title":"Tumor-initiating and metastasis-initiating cells of clear-cell renal cell carcinoma","volume":"32","author":"Pham","year":"2025","journal-title":"J. Biomed. Sci."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Kim, H., Shim, B.Y., Lee, S.-J., Lee, J.Y., Lee, H.-J., and Kim, I.-H. (2021). Loss of Von Hippel\u2013Lindau (VHL) Tumor Suppressor Gene Function: VHL\u2013HIF Pathway and Advances in Treatments for Metastatic Renal Cell Carcinoma (RCC). Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22189795"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Zhu, H., Wang, X., Lu, S., and Ou, K. (2023). Metabolic reprogramming of clear cell renal cell carcinoma. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1195500"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Yao, J.-t., Hu, P.-c., Li, X.-w., Xu, J.-c., Wang, K.-j., Ye, S.-z., Meng, X.-y., Chen, H.-c., Liang, Y., and Ma, Q. (Genes Dis., 2025). Research progress in metabolic reprogramming and targeting metabolic pathways for clear cell renal cell carcinoma, Genes Dis., in press.","DOI":"10.1016\/j.gendis.2025.101991"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1007\/s10238-025-02031-0","article-title":"Immunotherapy in clear cell renal cell carcinoma: Current Status, novel Strategies, and future perspectives","volume":"26","author":"Chen","year":"2026","journal-title":"Clin. Exp. Med."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"e70585","DOI":"10.1002\/mco2.70585","article-title":"Natural Products in Cancer Prevention and Therapy: Current Challenges and Future Directions","volume":"7","author":"Qian","year":"2026","journal-title":"MedComm"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Bianchi, N., Ancona, P., and Aguiari, G. (2025). Molecular Mechanisms of Drug Resistance in Clear Cell Renal Cell Carcinoma. Cancers, 17.","DOI":"10.3390\/cancers17101613"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Akuma, M., Kim, M., Zhu, C., Wiljer, E., Gaudreau-Lapierre, A., Patterson, L.D., Trinkle-Mulcahy, L., Stanford, W.L., Riazalhosseini, Y., and Russell, R.C. (2024). Loss of VHL-mediated pRb regulation promotes clear cell renal cell carcinoma. bioRxiv.","DOI":"10.1101\/2024.04.14.589424"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Zhang, Q., and Yang, H. (2012). The Roles of VHL-Dependent Ubiquitination in Signaling and Cancer. Front. Oncol., 2.","DOI":"10.3389\/fonc.2012.00035"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"4298","DOI":"10.1093\/emboj\/19.16.4298","article-title":"Mechanism of regulation of the hypoxia-inducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein","volume":"19","author":"Tanimoto","year":"2000","journal-title":"EMBO J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"e162480","DOI":"10.1172\/JCI162480","article-title":"Von Hippel-Lindau disease: Insights into oxygen sensing, protein degradation, and cancer","volume":"132","author":"Kaelin","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"102193","DOI":"10.1016\/j.tranon.2024.102193","article-title":"Advancements in understanding the molecular mechanisms and clinical implications of Von Hippel-Lindau syndrome: A comprehensive review","volume":"51","author":"Wang","year":"2025","journal-title":"Transl. Oncol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1016\/j.tibs.2025.06.005","article-title":"The HIF axes in cancer: Angiogenesis, metabolism, and immune-modulation","volume":"50","author":"Koh","year":"2025","journal-title":"Trends Biochem. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Liu, L., Yu, J., Liu, Y., Xie, L., Hu, F., and Liu, H. (2025). Hypoxia-driven angiogenesis and metabolic reprogramming in vascular tumors. Front. Cell Dev. Biol., 13.","DOI":"10.3389\/fcell.2025.1572909"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"32","DOI":"10.3892\/ijo.2026.5845","article-title":"Regulatory networks of HIFs in tumor-infiltrating immune cells: From molecular mechanisms to therapeutic implications","volume":"68","author":"Li","year":"2026","journal-title":"Int. J. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhan, M., Zhao, B., Chen, H., Wu, J., Shi, R., Gao, F., Zhao, L., and Zhu, J. (2025). Metabolic reprogramming in clear cell renal cell carcinoma: Core pathways and targeted therapeutic strategies. Front. Genet., 16.","DOI":"10.3389\/fgene.2025.1752384"},{"key":"ref_18","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_19","doi-asserted-by":"crossref","unstructured":"Zhu, Y., Liu, J., Qiu, F., You, Z., Liu, Z., Zeng, J., Zhong, J., Song, Z., Zhang, S., and Lu, J. (2026). The tumor microenvironment in leukemia: Molecular pathways of immune evasion. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1743920"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e173934","DOI":"10.1172\/JCI173934","article-title":"VHL loss reprograms the immune landscape to promote an inflammatory myeloid microenvironment in renal tumorigenesis","volume":"134","author":"Wolf","year":"2024","journal-title":"J. Clin. Investig."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1186\/s11658-024-00682-7","article-title":"Systematic and comprehensive insights into HIF-1 stabilization under normoxic conditions: Implications for cellular adaptation and therapeutic strategies in cancer","volume":"30","author":"Zhang","year":"2025","journal-title":"Cell. Mol. Biol. Lett."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kunachowicz, D., Tomecka, P., S\u0119dzik, M., Kalinin, J., Ku\u017anicki, J., and Rembia\u0142kowska, N. (2025). Influence of Hypoxia on Tumor Heterogeneity, DNA Repair, and Cancer Therapy: From Molecular Insights to Therapeutic Strategies. Cells, 14.","DOI":"10.3390\/cells14141057"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Bakleh, M.Z., and Al Haj Zen, A. (2025). The Distinct Role of HIF-1\u03b1 and HIF-2\u03b1 in Hypoxia and Angiogenesis. Cells, 14.","DOI":"10.3390\/cells14090673"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1080\/21541264.2024.2417475","article-title":"Hypoxia-inducible transcription factors: Architects of tumorigenesis and targets for anticancer drug discovery","volume":"16","author":"McDermott","year":"2025","journal-title":"Transcription"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"11296","DOI":"10.3390\/cimb46100671","article-title":"The Interplay between von Hippel-Lindau Tumor Suppressor Gene, Lon Protease, ROS Accumulation, and Inflammation in Clear Cell Renal Cell Carcinoma","volume":"46","author":"Tsai","year":"2024","journal-title":"Curr. Issues Mol. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1038\/s41419-021-03901-7","article-title":"VHL regulates the sensitivity of clear cell renal cell carcinoma to SIRT4-mediated metabolic stress via HIF-1\u03b1\/HO-1 pathway","volume":"12","author":"Tong","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"5571638","DOI":"10.1155\/2021\/5571638","article-title":"Loss of Function of von Hippel-Lindau Trigger Lipocalin 2-Dependent Inflammatory Responses in Cultured and Primary Renal Tubular Cells","volume":"2021","author":"Kuo","year":"2021","journal-title":"Oxid. Med. Cell. Longev."},{"key":"ref_28","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_29","doi-asserted-by":"crossref","first-page":"13036","DOI":"10.18632\/oncotarget.3675","article-title":"PI3K\/AKT\/mTOR pathway plays a major pathogenetic role in glycogen accumulation and tumor development in renal distal tubules of rats and men","volume":"6","author":"Ribback","year":"2015","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Badoiu, S.C., Greabu, M., Miricescu, D., Stanescu-Spinu, I.-I., Ilinca, R., Balan, D.G., Balcangiu-Stroescu, A.E., Mihai, D.A., Vacaroiu, I.A., and Stefani, C. (2023). PI3K\/AKT\/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL\/HIF Axis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms24098391"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1111\/imm.70045","article-title":"Molecular Mediators of Metabolic Reprogramming in Cancer: Mechanisms, Regulatory Networks, and Therapeutic Strategies","volume":"177","author":"Ahuja","year":"2026","journal-title":"Immunology"},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Reytor-Gonz\u00e1lez, C., Jim\u00e9nez-Flores, E., Gonz\u00e1lez, N., and Simancas-Racines, D. (2025). Redefining Chemoresistance: Natural Bioactives as Molecular Modulators at the Cancer\u2013Tumor Microenvironment Interface. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26168037"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"107099","DOI":"10.1016\/j.phrs.2024.107099","article-title":"Natural products for combating multidrug resistance in cancer","volume":"202","author":"Chen","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Ma, J., Wang, X., and Sun, Q. (2026). Beyond cytotoxicity: Molecular mechanisms of natural products as multi-targeting modulators and chemo-sensitizers in oncology. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1782874"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Feng, C., Lyu, Y., Gong, L., and Wang, J. (2022). Therapeutic Potential of Natural Products in the Treatment of Renal Cell Carcinoma: A Review. Nutrients, 14.","DOI":"10.3390\/nu14112274"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"2300025","DOI":"10.1002\/adbi.202300025","article-title":"Natural Compounds Derived from Plants on Prevention and Treatment of Renal Cell Carcinoma: A Literature Review","volume":"8","author":"Yin","year":"2024","journal-title":"Adv. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Mazumder, S., Higgins, P.J., and Samarakoon, R. (2023). Downstream Targets of VHL\/HIF-\u03b1 Signaling in Renal Clear Cell Carcinoma Progression: Mechanisms and Therapeutic Relevance. Cancers, 15.","DOI":"10.3390\/cancers15041316"},{"key":"ref_38","first-page":"1616","article-title":"The effect of curcumin on hypoxia in the tumour microenvironment as a regulatory factor in cancer","volume":"19","author":"Zahedi","year":"2023","journal-title":"Arch. Med. Sci. AMS"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e71452","DOI":"10.1002\/fsn3.71452","article-title":"Anticancer Molecular Mechanisms of Curcuminoids: An Updated Review of Clinical Trials","volume":"14","author":"Momal","year":"2026","journal-title":"Food Sci. Nutr."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"106981","DOI":"10.1016\/j.jff.2025.106981","article-title":"Role of resveratrol in the prevention and treatment of urological cancers: New perspectives on multiple molecular targets and signaling pathways","volume":"132","author":"Hosseini","year":"2025","journal-title":"J. Funct. Foods"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3158","DOI":"10.21037\/tcr-21-227","article-title":"Curcumin reverses the sunitinib resistance in clear cell renal cell carcinoma (ccRCC) through the induction of ferroptosis via the ADAMTS18 gene","volume":"10","author":"Xu","year":"2021","journal-title":"Transl. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.ejphar.2018.02.038","article-title":"Autophagy is a major mechanism for the dual effects of curcumin on renal cell carcinoma cells","volume":"826","author":"Deng","year":"2018","journal-title":"Eur. J. Pharmacol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"895","DOI":"10.2217\/epi-2023-0150","article-title":"Resveratrol affects ccRCC cell senescence and macrophage polarization by regulating the stability of CCNB1 by RBM15","volume":"15","author":"Chen","year":"2023","journal-title":"Epigenomics"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"102584","DOI":"10.1016\/j.tice.2024.102584","article-title":"Resveratrol enhances sensitivity of renal cell carcinoma to tivozanib: An in-vitro study","volume":"91","author":"Taheri","year":"2024","journal-title":"Tissue Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1186\/2045-824X-5-9","article-title":"EGCG, a major green tea catechin suppresses breast tumor angiogenesis and growth via inhibiting the activation of HIF-1\u03b1 and NF\u03baB, and VEGF expression","volume":"5","author":"Gu","year":"2013","journal-title":"Vasc. Cell"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Li, D., Cao, D., Sun, Y., Cui, Y., Zhang, Y., Jiang, J., and Cao, X. (2024). The roles of epigallocatechin gallate in the tumor microenvironment, metabolic reprogramming, and immunotherapy. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1331641"},{"key":"ref_47","first-page":"313","article-title":"Quercetin inhibits proliferation and migration of clear cell renal cell carcinoma cells by regulating TP53 gene","volume":"45","author":"Gao","year":"2025","journal-title":"Nan Fang Yi Ke Da Xue Xue Bao J. South. Med. Univ."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1056\/NEJMoa060655","article-title":"Sorafenib in advanced clear-cell renal-cell carcinoma","volume":"356","author":"Escudier","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.bbcan.2018.06.003","article-title":"Genetic and metabolic hallmarks of clear cell renal cell carcinoma","volume":"1870","author":"Sanchez","year":"2018","journal-title":"Biochim. Biophys. Acta Rev. Cancer"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Sureka, N., Maheshwari, R., Agravat, A., Singhal, S., Zaman, S., Rishi, B., Siraj, F., Zaheer, S., and Misra, A. (2026). Hypoxic microenvironment in cancer: Role in metabolic reprogramming. Front. Oncol., 16.","DOI":"10.3389\/fonc.2026.1771365"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Cui, Y., Li, C., Sang, F., Cao, W., Qin, Z., and Zhang, P. (2022). Natural products targeting glycolytic signaling pathways-an updated review on anti-cancer therapy. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.1035882"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1002\/cai2.7","article-title":"Crosstalk between ferroptosis and stress-Implications in cancer therapeutic responses","volume":"1","author":"Zhang","year":"2022","journal-title":"Cancer Innov."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"167","DOI":"10.3892\/or.2024.8826","article-title":"Flavonoids as modulators of metabolic reprogramming in renal cell carcinoma (Review)","volume":"52","author":"Shahzad","year":"2024","journal-title":"Oncol. Rep."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"639401","DOI":"10.1155\/2013\/639401","article-title":"Natural compounds as regulators of the cancer cell metabolism","volume":"2013","author":"Cerella","year":"2013","journal-title":"Int. J. Cell Biol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1769","DOI":"10.1038\/s41467-017-01965-8","article-title":"HIF drives lipid deposition and cancer in ccRCC via repression of fatty acid metabolism","volume":"8","author":"Du","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Huang, K., and Chen, K. (2026). Immune Escape in Renal Cell Carcinoma: Latest Research and Treatment Strategies. Int. J. Mol. Sci., 27.","DOI":"10.3390\/ijms27073064"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"21321","DOI":"10.1038\/s41598-025-08199-5","article-title":"Identification of CXCR4 as a potential preventive gene in clear cell renal cell carcinoma from machine learning and immune analysis","volume":"15","author":"Hu","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Kovaleva, O.V., Sinyov, V.V., Rashidova, M.A., Malashenko, O.S., and Gratchev, A. (2026). Tumor-associated neutrophils in renal cell carcinoma. Front. Immunol., 17.","DOI":"10.3389\/fimmu.2026.1755401"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"909","DOI":"10.1038\/s41591-020-0839-y","article-title":"Interplay of somatic alterations and immune infiltration modulates response to PD-1 blockade in advanced clear cell renal cell carcinoma","volume":"26","author":"Braun","year":"2020","journal-title":"Nat. Med."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"662","DOI":"10.1016\/j.ccell.2021.03.007","article-title":"Single-cell sequencing links multiregional immune landscapes and tissue-resident T cells in ccRCC to tumor topology and therapy efficacy","volume":"39","author":"Krishna","year":"2021","journal-title":"Cancer Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1158\/2159-8290.CD-24-0991","article-title":"Presence of Tertiary Lymphoid Structures and Exhausted Tissue-Resident T Cells Determines Clinical Response to PD-1 Blockade in Renal Cell Carcinoma","volume":"15","author":"Hugaboom","year":"2025","journal-title":"Cancer Discov."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1158\/1078-0432.CCR-23-2274","article-title":"PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients","volume":"30","author":"Denize","year":"2024","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1007\/s00262-025-04132-x","article-title":"VHL restoration in clear cell renal cell carcinoma improves NK cell infiltration and function","volume":"74","author":"Tong","year":"2025","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Huo, J.-L., Fu, W.-J., Liu, Z.-H., Lu, N., Jia, X.-Q., and Liu, Z.-S. (2022). Research advance of natural products in tumor immunotherapy. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.972345"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Hong, C.-E., and Lyu, S.-Y. (2025). Immunomodulatory Natural Products in Cancer Organoid-Immune Co-Cultures: Bridging the Research Gap for Precision Immunotherapy. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26157247"},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Yao, P., Liang, S., Liu, Z., and Xu, C. (2024). A review of natural products targeting tumor immune microenvironments for the treatment of lung cancer. Front. Immunol., 15.","DOI":"10.3389\/fimmu.2024.1343316"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.cbi.2016.06.027","article-title":"Oxidative stress, polarization of macrophages and tumour angiogenesis: Efficacy of caffeic acid","volume":"256","author":"Kukolj","year":"2016","journal-title":"Chem.-Biol. Interact."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"107788","DOI":"10.1016\/j.phrs.2025.107788","article-title":"Targeting tumor-associated macrophage polarization with traditional Chinese medicine active ingredients: Dual reversal of chemoresistance and immunosuppression in tumor microenvironment","volume":"216","author":"Qi","year":"2025","journal-title":"Pharmacol. Res."},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Li, W., Qi, Y., Li, Y., Liu, L., Dong, X., and Li, B. (2025). Resveratrol suppresses OSCC invasion and migration by regulating macrophage polarization via Syk signaling pathway. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1660851"},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Han, Y., Jo, H., Cho, J.H., Dhanasekaran, D.N., and Song, Y.S. (2019). Resveratrol as a Tumor-Suppressive Nutraceutical Modulating Tumor Microenvironment and Malignant Behaviors of Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20040925"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"939","DOI":"10.1038\/ki.2009.296","article-title":"The role of VHL in clear-cell renal cell carcinoma and its relation to targeted therapy","volume":"76","author":"Clark","year":"2009","journal-title":"Kidney Int."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1038\/s41392-025-02280-1","article-title":"Immune evasion in cancer: Mechanisms and cutting-edge therapeutic approaches","volume":"10","author":"Tufail","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Cinque, A., Minnei, R., Floris, M., and Trevisani, F. (2022). The Clinical and Molecular Features in the VHL Renal Cancers; Close or Distant Relatives with Sporadic Clear Cell Renal Cell Carcinoma?. Cancers, 14.","DOI":"10.3390\/cancers14215352"},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41581-020-00359-2","article-title":"Clear cell renal cell carcinoma ontogeny and mechanisms of lethality","volume":"17","author":"Jonasch","year":"2021","journal-title":"Nat. Rev. Nephrol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1007\/s11427-017-9178-y","article-title":"Hypoxia inducible factor (HIF) in the tumor microenvironment: Friend or foe?","volume":"60","author":"Huang","year":"2017","journal-title":"Sci. China Life Sci."},{"key":"ref_76","doi-asserted-by":"crossref","unstructured":"Vito, A., El-Sayes, N., and Mossman, K. (2020). Hypoxia-Driven Immune Escape in the Tumor Microenvironment. Cells, 9.","DOI":"10.3390\/cells9040992"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4584\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T04:21:41Z","timestamp":1779510101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/10\/4584"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,20]]},"references-count":76,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["ijms27104584"],"URL":"https:\/\/doi.org\/10.3390\/ijms27104584","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,20]]}}}