Targeting CD70 in cancer: Mechanisms of immune escape and translational opportunities

Abstract

CD70, a tightly regulated immune co-stimulatory ligand under physiological conditions, becomes aberrantly and persistently overexpressed in a wide spectrum of malignancies, including renal cell carcinoma (RCC), glioblastoma and acute myeloid leukaemia. This tumour-restricted expression pattern, coupled with its potent immunomodulatory effects, positions CD70 as a uniquely actionable target in modern oncology. Unlike classical immune checkpoints, CD70 contributes to immune escape by chronically engaging CD27, leading to T cell exhaustion, regulatory T cell (Treg) expansion and myeloid-derived suppressor cell activation, collectively shaping a profoundly immunosuppressive tumour microenvironment. Mechanistically, CD70 expression is amplified by convergent oncogenic, inflammatory and hypoxic signals, most notably HIF-2α stabilization in VHL-deficient RCC, linking it to aggressive disease biology and poor prognosis. Notably, CD70 expression in tumours often coexists with dysregulation of receptor tyrosine kinase (RTK) pathways (e.g. MET, AXL) and immune checkpoint circuits (e.g. PD-1/PD-L1), supporting rationale combination therapies aimed at overcoming resistance and enhancing anti-tumour immunity. A diverse array of CD70-directed therapies, including antibody-drug conjugates, CAR-T and CAR-NK cells, monoclonal antibodies and radiotheranostic agents, are advancing through preclinical and early clinical pipelines. Beyond therapeutic applications, CD70 also holds promise as a biomarker for tumour detection, patient stratification and response monitoring. This mini-review synthesizes emerging insights into CD70-driven immune evasion, highlights evolving therapeutic strategies and discusses the integration of CD70 targeting into next-generation immunotherapy and precision oncology platforms. This review is novel in linking CD70-mediated immune escape to oncogenic RTK signalling and in foregrounding recent translational advances and rational combination strategies that have not been comprehensively covered in prior reviews.

Keywords

CD27 / CD70 / immune checkpoint / immune evasion / renal cell carcinoma

References

[1] Galassi C, Chan TA, Vitale I, Galluzzi L. The hallmarks of cancer immune evasion. Cancer Cell. 2024; 42(11): 1825-1863.

[2] Zhang M, Liu C, Tu J, et al. Advances in cancer immunotherapy: historical perspectives, current developments, and future directions. Mol Cancer. 2025; 24(1): 136.

[3] Flieswasser T, Camara-Clayette V, Danu A, et al. Screening a broad range of solid and haematological tumour types for CD70 expression using a uniform IHC methodology as potential patient stratification method. Cancers (Basel). 2019; 11(10): 1611.

[4] Tesselaar K, Gravestein LA, van Schijndel GM, Borst J, van Lier RA. Characterization of murine CD70, the ligand of the TNF receptor family member CD27. J Immunol. 1997; 159(10): 4959-4965.

[5] Flieswasser T, Van den Eynde A, Van Audenaerde J, et al. The CD70-CD27 axis in oncology: the new kids on the block. J Exp Clin Cancer Res. 2022; 41(1): 12.

[6] Huang RR, Chen Z, Kroeger N, et al. CD70 is consistently expressed in primary and metastatic clear cell renal cell carcinoma. Clin Genitourinary Cancer. 2024; 22(2): 347-353.

[7] Seyfrid M, Maich WT, Shaikh VM, et al. CD70 as an actionable immunotherapeutic target in recurrent glioblastoma and its microenvironment. J Immunother Cancer. 2022; 10(1):e003289.

[8] Nie M, Ren W, Ye X, et al. The dual role of CD70 in B-cell lymphomagenesis. Clin Transl Med. 2022; 12(12):e1118.

[9] Liu K, Yang Q, Liu P, et al. CD70 is a potential prognostic marker and significantly regulates cellular function in diffuse large B-cell lymphoma. PLoS One. 2024; 19(10):e0312445.

[10] Arroyo Hornero R, Georgiadis C, Hua P, et al. CD70 expression determines the therapeutic efficacy of expanded human regulatory T cells. Commun Biol. 2020; 3(1): 375.

[11] Wu G, Guo S, Luo Q, et al. Preclinical evaluation of CD70-specific CAR T cells targeting acute myeloid leukemia. Front Immunol. 2023; 14:1093750.

[12] Pal SK, Tran B, Haanen JBAG, et al. CD70-targeted allogeneic CAR T-cell therapy for advanced clear cell renal cell carcinoma. Cancer Discov. 2024; 14(7): 1176-1189.

[13] Wu CH, Wang L, Yang CY, et al. Targeting CD70 in cutaneous T-cell lymphoma using an antibody-drug conjugate in patient-derived xenograft models. Blood Adv. 2022; 6(7): 2290-2302.

[14] Zhou X, Wu Q, Zhai W, et al. CD70-targeted immuno-PET/CT imaging of clear cell renal cell carcinoma: a translational study. J Nucl Med. 2024; 65(12): 1891-1898.

[15] Chen S-S, Yan X-J, Van Rompaey L, Zabrocki P, Chiorazzi N. Anti-CD70 monoclonal antibodies show efficacy in preclinical models for chronic lymphoblastic leukemia. Blood. 2022; 140(Supplement 1): 1803-1804.

[16] Wei W, Grünwald V, Herrmann K. CD70-targeted cancer theranostics: progress and challenges. Medicine. 2025; 6(8):100671.

[17] Ruf M, Mittmann C, Nowicka AM, et al. pVHL/HIF-regulated CD70 expression is associated with infiltration of CD27+ lymphocytes and increased serum levels of soluble CD27 in clear cell renal cell carcinoma. Clin Cancer Res. 2015; 21(4): 889-898.

[18] Borst J, Hendriks J, Xiao Y. CD27 and CD70 in T cell and B cell activation. Curr Opin Immunol. 2005; 17(3): 275-281.

[19] Van Deusen KE, Rajapakse R, Bullock TN. CD70 expression by dendritic cells plays a critical role in the immunogenicity of CD40-independent, CD4+ T cell-dependent, licensed CD8+ T cell responses. J Leukoc Biol. 2010; 87(3): 477-485.

[20] Rey C, Jones KL, Stacey KB, et al. CD8α and CD70 mark human natural killer cell populations which differ in cytotoxicity. Front Immunol. 2025; 16:1526379.

[21] Uhlén M, Björling E, Agaton C, et al. A human protein atlas for normal and cancer tissues based on antibody proteomics. Mol Cell Proteomics. 2005; 4(12): 1920-1932.

[22] Uhlén M, Fagerberg L, Hallström BM, et al. Proteomics. Tissue-based map of the human proteome. Science. 2015; 347(6220):1260419.

[23] Uhlen M, Karlsson MJ, Zhong W, et al. A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science. 2019; 366(6472):eaax9198.

[24] Shaffer DR, Savoldo B, Yi Z, et al. T cells redirected against CD70 for the immunotherapy of CD70-positive malignancies. Blood. 2011; 117(16): 4304-4314.

[25] Al Sayed MF, Ruckstuhl CA, Hilmenyuk T, et al. CD70 reverse signaling enhances NK cell function and immunosurveillance in CD27-expressing B-cell malignancies. Blood. 2017; 130(3): 297-309.

[26] Grant EJ, Nüssing S, Sant S, Clemens EB, Kedzierska K. The role of CD27 in anti-viral T-cell immunity. Curr Opin Virol. 2017; 22: 77-88.

[27] Welten Suzanne PM, Redeker A, Franken Kees L, et al. CD27-CD70 costimulation controls T cell immunity during acute and persistent cytomegalovirus infection. J Virol. 2013; 87(12): 6851-6865.

[28] Lee W-W, Yang Z-Z, Li G, Weyand CM, Goronzy J. Unchecked CD70 expression on T cells lowers threshold for T cell activation in rheumatoid arthritis. J Immunol. 2007; 179(4): 2609-2615.

[29] Arimoto-Miyamoto K, Kadowaki N, Kitawaki T, Iwata S, Morimoto C, Uchiyama T. Optimal stimulation for CD70 induction on human monocyte-derived dendritic cells and the importance of CD70 in naive CD4+ T-cell differentiation. Immunology. 2010; 130(1): 137-149.

[30] Yu SE, Park SH, Jang YK. Epigenetic silencing of TNFSF7 (CD70) by DNA methylation during progression to breast cancer. Mol Cells. 2010; 29(2): 217-221.

[31] Kitajima S, Lee KL, Fujioka M, et al. Hypoxia-inducible factor-2 alpha up-regulates CD70 under hypoxia and enhances anchorage-independent growth and aggressiveness in cancer cells. Oncotarget. 2018; 9(27): 19123-19135.

[32] Riether C, Schürch CM, Flury C, et al. Tyrosine kinase inhibitor-induced CD70 expression mediates drug resistance in leukemia stem cells by activating Wnt signaling. Sci Transl Med. 2015; 7(298):298ra119.

[33] Nilsson MB, Yang Y, Heeke S, et al. CD70 is a therapeutic target upregulated in EMT-associated EGFR tyrosine kinase inhibitor resistance. Cancer Cell. 2023; 41(2): 340-355.

[34] Shiomi M, Matsuzaki S, Serada S, et al. CD70 antibody-drug conjugate: a potential novel therapeutic agent for ovarian cancer. Cancer Sci. 2021; 112(9): 3655-3668.

[35] Zhang X, Hong B, Yu W, et al. Comprehensive pan-cancer analysis reveals CD70 as a promising therapeutic target and biomarker in clear cell renal cell carcinoma. Int J Biol Macromol. 2025; 307:142079.

[36] Chandrashekar DS, Karthikeyan SK, Korla PK, et al. UALCAN: an update to the integrated cancer data analysis platform. Neoplasia. 2022; 25: 18-27.

[37] Chandrashekar DS, Bashel B, Balasubramanya SAH, et al. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia. 2017; 19(8): 649-658.

[38] Ding S, Qiao N, Zhu Q, et al. Single-cell atlas reveals a distinct immune profile fostered by T cell-B cell crosstalk in triple negative breast cancer. Cancer Commun (Lond). 2023; 43(6): 661-684.

[39] Diegmann J, Junker K, Loncarevic IF, Michel S, Schimmel B, von Eggeling F. Immune escape for renal cell carcinoma: CD70 mediates apoptosis in lymphocytes. Neoplasia. 2006; 8(11): 933-938.

[40] Bowakim-Anta N, Acolty V, Azouz A, et al. Chronic CD27-CD70 costimulation promotes type 1-specific polarization of effector Tregs. Front Immunol. 2023; 14: 2023.

[41] Sauer T, Parikh K, Sharma S, et al. CD70-specific CAR T cells have potent activity against acute myeloid leukemia without HSC toxicity. Blood. 2021; 138(4): 318-330.

[42] Keller AM, Xiao Y, Peperzak V, Naik SH, Borst J. Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting. Blood. 2009; 113(21): 5167-5175.

[43] Keller AM, Schildknecht A, Xiao Y, van den Broek M, Borst J. Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity. Immunity. 2008; 29(6): 934-946.

[44] Taraban VY, Rowley TF, Tough DF, Al-Shamkhani A. Requirement for CD70 in CD4+ Th cell-dependent and innate receptor-mediated CD8+ T cell priming. J Immunol. 2006; 177(5): 2969-2975.

[45] Claus C, Riether C, Schürch C, Matter MS, Hilmenyuk T, Ochsenbein AF. CD27 signaling increases the frequency of regulatory T cells and promotes tumor growth. Cancer Res. 2012; 72(14): 3664-3676.

[46] Gong L, Luo J, Zhang Y, et al. Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70−CD27 interaction. Nat Commun. 2023; 14(1): 1912.

[47] Inaguma S, Lasota J, Czapiewski P, et al. CD70 expression correlates with a worse prognosis in malignant pleural mesothelioma patients via immune evasion and enhanced invasiveness. J Pathol. 2020; 250(2): 205-216.

[48] Ortiz-Cuaran S, Swalduz A, Foy JP, et al. Epithelial-to-mesenchymal transition promotes immune escape by inducing CD70 in non-small cell lung cancer. Eur J Cancer. 2022; 169: 106-122.

[49] Sam I, Ben Hamouda N, Alkatrib M, et al. The CD70–CD27 axis in cancer immunotherapy: predictive biomarker and therapeutic target. Clin Cancer Res. 2025; 31(14): 2872-2881.

[50] Pal SK, Forero-Torres A, Thompson JA, et al. A phase 1 trial of SGN-CD70A in patients with CD70-positive, metastatic renal cell carcinoma. Cancer. 2019; 125(7): 1124-1132.

[51] Phillips T, Barr PM, Park SI, et al. A phase 1 trial of SGN-CD70A in patients with CD70-positive diffuse large B cell lymphoma and mantle cell lymphoma. Invest New Drugs. 2019; 37(2): 297-306.

[52] Owonikoko TK, Hussain A, Stadler WM, et al. A phase 1 multicenter open-label dose-escalation study of BMS-936561 (MDX-1203) in clear cell renal cell carcinoma (ccRCC) and B-cell non Hodgkin lymphoma (B-NHL). J Clin Oncol. 2014; 32(15):2558.

[53] Jin L, Ge H, Long Y, et al. CD70, a novel target of CAR T-cell therapy for gliomas. Neuro Oncol. 2018; 20(1): 55-65.

[54] Xiong Q, Wang H, Shen Q, et al. The development of chimeric antigen receptor T-cells against CD70 for renal cell carcinoma treatment. J Transl Med. 2024; 22(1): 368.

[55] Hu J, Li J, Yang B, et al. CD70: an emerging target for integrated cancer diagnosis and therapy. Clin Transl Med. 2025; 15(7):e70400.

[56] Riether C, Pabst T, Höpner S, et al. Targeting CD70 with cusatuzumab eliminates acute myeloid leukemia stem cells in patients treated with hypomethylating agents. Nat Med. 2020; 26(9): 1459-1467.

[57] Zhou X, Wu Q, Zhai W, et al. CD70-targeted immuno-PET/CT imaging of clear cell renal cell carcinoma: a translational study. J Nucl Med. 2024; 65(12): 1891-1898.

[58] Tesselaar K, Arens R, van Schijndel GMW, et al. Lethal T cell immunodeficiency induced by chronic costimulation via CD27−CD70 interactions. Nat Immunol. 2003; 4(1): 49-54.

[59] Zhou L, Liu XD, Sun M, et al. Targeting MET and AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. Oncogene. 2016; 35(21): 2687-2697.

[60] Sabarwal A, Machaalani M, Rawat L, et al. Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress. Cancer Lett. 2025; 633:217984.

[61] Organ SL, Tsao MS. An overview of the c-MET signaling pathway. Ther Adv Med Oncol. 2011; 3(1): S7-S19.

[62] Goyette MA, Elkholi IE, Apcher C, et al. Targeting Axl favors an antitumorigenic microenvironment that enhances immunotherapy responses by decreasing Hif-1α levels. Proc Natl Acad Sci U S A. 2021; 118(29):e2023868118.

[63] Marques-Piubelli ML, Kumar B, Basar R, et al. Increased expression of CD70 in relapsed acute myeloid leukemia after hypomethylating agents. Virchows Arch. 2024; 485(5): 937-941.

RIGHTS & PERMISSIONS

2025 The Author(s). Clinical and Translational Discovery published by John Wiley & Sons Australia, Ltd on behalf of Shanghai Institute of Clinical Bioinformatics.