The DOI matches its Crossref record; 63 of the 63 references it cites were found in a registry or an index.
CDK4/6 Inhibition Augments Antitumor Immunity by Enhancing T-cell Activation
Open accessPublished version of a preprint
Abstract
Immune checkpoint blockade, exemplified by antibodies targeting the PD-1 receptor, can induce durable tumor regressions in some patients. To enhance the efficacy of existing immunotherapies, we screened for small molecules capable of increasing the activity of T cells suppressed by PD-1. Here, we show that short-term exposure to small-molecule inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6) significantly enhances T-cell activation, contributing to antitumor effects in vivo, due in part to the derepression of NFAT family proteins and their target genes, critical regulators of T-cell function. Although CDK4/6 inhibitors decrease T-cell proliferation, they increase tumor infiltration and activation of effector T cells. Moreover, CDK4/6 inhibition augments the response to PD-1 blockade in a novel ex vivo organotypic tumor spheroid culture system and in multiple in vivo murine syngeneic models, thereby providing a rationale for combining CDK4/6 inhibitors and immunotherapies. Significance: Our results define previously unrecognized immunomodulatory functions of CDK4/6 and suggest that combining CDK4/6 inhibitors with immune checkpoint blockade may increase treatment efficacy in patients. Furthermore, our study highlights the critical importance of identifying complementary strategies to improve the efficacy of immunotherapy for patients with cancer. Cancer Discov; 8(2); 216–33. ©2017 AACR. See related commentary by Balko and Sosman, p. 143. See related article by Jenkins et al., p. 196. This article is highlighted in the In This Issue feature, p. 127
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“cyclin-dependent kinase inhibitors 4 and 6 (CDK4/6) facilitate T cell activation, resulting in a higher number of tumour-infiltrating T cells in PDOs, cultivated over several days in a microfluidic 3D chip setup.”
From Human disease models in drug development (2023) · cites this paper as [129]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“CDK4/6 inhibition also showed high in vitro and in vivo activity and synergy with anti-PD-1 blocking antibodies129.”
From Human disease models in drug development (2023) · cites this paper as [129]
In the citing paper
“activation of effector T (TEFF) cells upon nuclear factor of activated T cells 1 (NFATC1, best known as NFAT) signaling and interleukin-2 (IL2) secretion (Deng et al., 2018)”
From Immunomodulation by targeted anticancer agents (2021) · cites this paper as Deng et al., 2018
In the citing paper
“CDK4/6 inhibition is also able to stimulate PD-1 expressing T-cells in vitro and enhance T cell infiltration (Deng et al., 2017).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Deng et al., 2017
In the citing paper
“This enhancement is driven at least in part by CDK6-induced phosphorylation of NFAT4.”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Deng et al., 2017
In the citing paper
“Combining palbociclib with a PD-1 blockade enhanced tumor regression and improved overall survival in mouse xenograft models of colon adenocarcinoma (Deng et al., 2017; Zhang et al., 2018).”
From CDK4/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought (2018) · cites this paper as Deng et al., 2017
In the citing paper
“CDK4/6 inhibitors improved the efficacy of α-PD-1 in murine models by enhancing lymphocyte infiltration and TIL activities [245–248].”
From Combination strategies with PD-1/PD-L1 blockade: current advances and future directions (2022) · cites this paper as [248]
In the citing paper
“We also recently demonstrated that CDK6, but not CDK4, phosphorylates NFAT family transcription factors to promote T cell activation and enhance the anti-tumor immune response[7].”
From Development of dual and selective degraders of cyclin-dependent kinases 4 and 6 (2019) · cites this paper as [7]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
STAR: ultrafast universal RNA-seq aligner
Dobin, A., Davis, C. A., Schlesinger, F., Drenkow, J., Zaleski, C., Jha, S., Batut, P., Chaisson, M., & Gingeras, T. R. (2013) · Bioinformatics · doi:10.1093/bioinformatics/bts635 · Cited by 51,709
PD-1 and PD-L1 Immune Checkpoint Blockade to Treat Breast Cancer
Hartkopf, A. D., Taran, F., Wallwiener, M., Walter, C. B., Krämer, B., Grischke, E., & Brucker, S. Y. (2016) · Breast Care · doi:10.1159/000453569 · Cited by 30,989
Adverse Renal Effects of Immune Checkpoint Inhibitors: A Narrative Review
Wanchoo, R., Karam, S., Uppal, N. N., Barta, V. S., Deray, G., Devoe, C., Launay‐Vacher, V., Jhaveri, K. D., & on behalf of Cancer and Kidney International Network Workgroup on Immune Checkpoint Inhibitors (2017) · American Journal of Nephrology · doi:10.1159/000455014 · Cited by 15,320
The blockade of immune checkpoints in cancer immunotherapy
Pardoll, D. M. (2012) · Nature Reviews Cancer · doi:10.1038/nrc3239 · Cited by 13,838 · cited 12×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundInfluentialNear-optimal probabilistic RNA-seq quantification
Bray, N. L., Pimentel, H., Melsted, P., & Pachter, L. (2016) · Nature Biotechnology · doi:10.1038/nbt.3519 · Cited by 9,723 · cited 11×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundMethodInfluentialNivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer
Borghaei, H., Paz-Ares, L., Horn, L., Spigel, D. R., Steins, M., Ready, N. E., Chow, L. Q., Vokes, E. E., Felip, E., Holgado, E., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1507643 · Cited by 9,335 · cited 11×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundInfluentialMutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer
Rizvi, N. A., Hellmann, M. D., Snyder, A., Kvistborg, P., Makarov, V., Havel, J. J., Lee, W., Yuan, J., Wong, P., Ho, T. S., et al. (2015) · Science · doi:10.1126/science.aaa1348 · Cited by 7,802
Pembrolizumab versus Ipilimumab in Advanced Melanoma
Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L., Daud, A., Carlino, M. S., McNeil, C., Lotem, M., et al. (2015) · New England Journal of Medicine · doi:10.1056/nejmoa1503093 · Cited by 5,887 · cited 11×
“The digested NFATc3 and His-GB1 were separated and further purified using size exclusion chromatography (GE Healthcare Life Sciences “Superdex 75 10/300 GL”).”
BackgroundInfluentialTumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion
Dong, H., Strome, S. E., Salomao, D. R., Tamura, H., Hirano, F., Flies, D. B., Roche, P. C., Lu, J., Zhu, G., Tamada, K., et al. (2002) · Nature Medicine · doi:10.1038/nm730 · Cited by 5,025 · cited 3×
“The discovery of immune checkpoint receptors, such as CTLA-4 and PD-1 (5-9), that repress the activity of anti-tumor T cells, led to the development of blocking antibodies directed against these co-inhibitory receptors or their ligands, including ipilimumab (anti-CTLA-4), pembrolizumab (anti-PD-1), nivolumab (anti-PD1…”
BackgroundNeoantigens in cancer immunotherapy
Schumacher, T. N., & Schreiber, R. D. (2015) · Science · doi:10.1126/science.aaa4971 · Cited by 4,783 · cited 11×
“As Kras mutant GEMMs are not responsive to checkpoint blockade (3,44), in part due to a low levels of somatic mutations (45), we utilized the murine syngeneic colon adenocarcinoma model MC38.”
BackgroundMethodInfluential
Cited by
Sorted by citations
Items 301–400 of 776
Al-Qasem, A. J., Alves, C. L., & Ditzel, H. J. (2021) · Cancers · doi:10.3390/cancers13215397 · Cited by 25
“Additionally, CDK4/6i can enhance the activity of effector T-cells through activation of NFAT transcription factors and their targeted genes, particularly IL-2 [75].”
BackgroundKrasniqi, E., Goeman, F., Pulito, C., Palcau, A. C., Ciuffreda, L., Lisa, F. S. D., Filomeno, L., Barba, M., Pizzuti, L., Cappuzzo, F., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232314534 · Cited by 23
Nguyen, T. T., Katt, W. P., & Cerione, R. A. (2022) · Future Drug Discovery · doi:10.4155/fdd-2022-0011 · Cited by 23
“Upon inhibition or depletion of the key cell cycle regulators CDK4 or CDK6 in colorectal cancer cells, there is an increase in myc expression, leading to an enhancement in glycolysis and mitochondrial glutamine metabolism [99].”
ResultYang, L., Chen, X., Lee, C., Shi, J., Lawrence, E. B., Zhang, L., Li, Y., Gao, N., Jung, S. Y., Creighton, C. J., et al. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02689-y · Cited by 24
“Recent studies have suggested that the efficacy of PD-L1 blockade requires tumor cell-intrinsic cell-cycle arrest to achieve long-lasting responses [52, 53].”
BackgroundZhao, S., Zhou, L., Dicker, D. T., Lev, A., Zhang, S., Ross, E. A., & El‐Deiry, W. S. (2021) · Scientific Reports · doi:10.1038/s41598-021-00150-8 · Cited by 22
Liu, J., Wang, X., Deng, Y., Yu, X., Wang, H., & Li, Z. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.766248 · Cited by 23
“(164) indicated that palbociclib or trilaciclib (another CDK4/6 inhibitor) significantly enhances Tconv cell activation, thus contributing to antitumor effects in vivo.”
BackgroundTissue-adhesive hydrogel for multimodal drug release to immune cells in skin
Day, N. B., Dalhuisen, R., Loomis, N. E., Adzema, S. G., Prakash, J., & Shields, C. W. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2022.07.053 · Cited by 22
Pandey, P., Khan, F., Upadhyay, T. K., & Sharangi, A. B. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24032236 · Cited by 24
“Greater nuclear NFAT expression and enhanced transcriptional activity driven by CDK4/6 inhibition altered the cytokine setting in the tumour microenvironment and promoted the activation of effector T cells [24,76].”
BackgroundPriming a vascular-selective cytokine response permits CD8+ T-cell entry into tumors
Kim, D. J., Anandh, S., Null, J. L., Przanowski, P., Bhatnagar, S., Kumar, P., Shelton, S. E., Grundy, E. E., Chiappinelli, K. B., Kamm, R. D., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-37807-z · Cited by 24
“As predicted, the addition of ICB with CDK4/6 and PI3Kalpha inhibitors enhances anti-tumor immune responses, further supporting the concept that combinatorial approaches targeting both the cell cycle and pathways that augment T-cell function are synergistic 58 .”
Self-citationKumar, A., Ramani, V., Bharti, V., Bellan, D. D. L., Saleh, N., Uzhachenko, R. V., Shen, C., Arteaga, C. L., Richmond, A. J., Reddy, S. M., et al. (2023) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2022-006019 · Cited by 23
The Evolving Pathways of the Efficacy of and Resistance to CDK4/6 Inhibitors in Breast Cancer
Gomes, I., Abreu, C., Costa, L., & Casimiro, S. (2023) · Cancers · doi:10.3390/cancers15194835 · Cited by 24
“…with CDK4/6i could repress regulatory T cells (Treg) proliferation [79,106–108], activate CD8+ T cells [79,106,109–111] and increase infiltration of effector T cells (Teff) on tumor microenvironment (TME) via the upregulation of the nuclear factor of activated T cells (NFAT) signaling [104,107].”
Synergistic targeting strategies for prostate cancer
Li, X., Han, Z., & Ai, J. (2025) · Nature Reviews Urology · doi:10.1038/s41585-025-01042-6 · Cited by 22
“Thus, the activation and tumour infiltration of effector T cells were potentiated by CDK4–CDK6 inhibition, although T cell proliferation was decreased 378 .”
Targeting CDK4/6 in mantle cell lymphoma
Lee, C. Y., Huang, X., Liberto, M. D., Martin, P., & Chen‐Kiang, S. (2020) · Annals of Lymphoma · doi:10.21037/aol.2019.12.01 · Cited by 19
“Deng and colleagues identified CDK4/6 inhibitors through a small-molecule screen as a class of compounds that could activate PD-1overexpressing Jurkat T cells, and treatment with CDK4/6 inhibitors increased infiltration of CD4 and CD8 T cells as well as the levels of Th1 cytokines in a mouse model of lung cancer (37).”
BackgroundNeoadjuvant immunotherapy in breast cancer: a paradigm shift?
Fountzila, E., & Ignatiadis, M. (2020) · ecancermedicalscience · doi:10.3332/ecancer.2020.1147 · Cited by 20
Li, Q., Chen, L., Ma, Y., Jian, X., Ji, J., You, W., & Zhao, P. (2021) · Bioorganic Chemistry · doi:10.1016/j.bioorg.2021.105324 · Cited by 21
Muttiah, C., Whittle, J. R., Oakman, C. A., & Lindeman, G. J. (2022) · Future Oncology · doi:10.2217/fon-2021-1450 · Cited by 21
Wu, Y., Shrestha, P., Heape, N. M., & Yarchoan, R. (2022) · Journal of Translational Medicine · doi:10.1186/s12967-022-03400-z · Cited by 22
“Recently, several studies indicated that in addition to inhibiting cell proliferation, CDK4/6 inhibitors may upregulate genes encoding MHC-I and the antigen presentation pathway in breast or colon tumors [23], or alter the tumor microenvironment by suppression of regulatory T cell proliferation [23, 34, 35], or enhanc…”
BackgroundChen, K., Li, Y., Wang, B., Yan, X., Tao, Y., Song, W., Xi, Z., He, K., & Xia, Q. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1101324 · Cited by 22
“In microfluidic PDOTS, the response to PD-1 blockade and novel combination therapies was examined, suggesting that CDK4/6 inhibition augmented the response to PD-1 blockade (101, 102).”
BackgroundYu, Z., Deng, P., Chen, Y., Lin, D., Liu, S., Hong, J., Guan, P., Chen, J., Zhong, M., Chen, J., et al. (2024) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2304619121 · Cited by 23
Estrogen receptor regulation of the immune microenvironment in breast cancer
McGuinness, C., & Britt, K. L. (2024) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2024.106517 · Cited by 25
Zhou, Z., Lei, J., Fang, J., Chen, P., Zhou, J., Wang, H., Sun, Z., Chen, Y., & Yin, L. (2024) · International Immunopharmacology · doi:10.1016/j.intimp.2024.112637 · Cited by 22
Breast cancer organoids and their applications for precision cancer immunotherapy
Guan, D., Liu, X., Shi, Q., He, B., Zheng, C., & Meng, X. (2023) · World Journal of Surgical Oncology · doi:10.1186/s12957-023-03231-2 · Cited by 20
“Cultivation and assessment of MDOTS/PDOTS from syngeneic immunoreactive murine models and tumor samples of patients are achieved for 1–2 weeks, such as Merkel cell carcinoma and melanoma [56, 57].”
MethodGarrido-Castro, A. C., Graham, N., Ali, L. R., Herold, C. I., Desrosiers, J., Do, K., Parsons, H. A., Li, T., Goel, S., DiLullo, M. K., et al. (2025) · Journal for ImmunoTherapy of Cancer · doi:10.1136/jitc-2024-010430 · Cited by 20
“26 28 These studies provide rationale supporting the combination of CDK4/6 inhibitors and immune checkpoint blockade.”
Self-citationGao, T., Sun, Y., Leng, P., Liu, D., Guo, Q., & Li, J. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1549520 · Cited by 22
“Mechanistically, CDK4/6 inhibitors potentiate T-cell responses via nuclear factor of activated T cells (NFAT) activation: they induce IL-2 secretion and phosphorylate NFAT to upregulate CXCL9/CXCL10 chemokines, facilitating T-cell in fi ltration (Zhang et al., 2018; Deng et al., 2018).”
Breaking Cancer’s Momentum: CDK4/6 Inhibitors and the Promise of Combination Therapy
Liu, Y., Park, S., & Li, Y. (2025) · Cancers · doi:10.3390/cancers17121941 · Cited by 21
“Studies have shown that short-term exposure to CDK4/6 inhibitors stimulates T-cell activation by suppressing NFAT transcription factors and improves memory T cells, a key factor in durable antitumor responses [86,87].”
Dominijanni, A. J., Mazzocchi, A. R., Shelkey, E., Forsythe, S. D., Devarasetty, M., & Söker, S. (2020) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2020.03.005 · Cited by 20
Padhye, A., Konen, J. M., Rodriguez, B. L., Fradette, J. J., Ochieng, J. K., Diao, L., Wang, J., Lü, W., Solis, L. S., Batra, H., et al. (2021) · JCI Insight · doi:10.1172/jci.insight.148392 · Cited by 22
“CDK4 inhibitors also enhanced effector T cell infiltration and activation (58).”
Song, X., & Lin, Q. (2022) · Technology in Cancer Research & Treatment · doi:10.1177/15330338221090351 · Cited by 23
Goel, S., Tan, A. R., Rugo, H. S., Aftimos, P. G., Andric, Z. G., Beelen, A. P., Zhang, J., Yi, J. S., Malik, R. K., & O’Shaughnessy, J. (2022) · Future Oncology · doi:10.2217/fon-2022-0773 · Cited by 20
Zhang, Z., Wang, G., Zhong, K., Chen, Y., Yang, N., Lu, Q., Yuan, B., Wang, Z., Li, H., Guo, L., et al. (2023) · Journal of Translational Medicine · doi:10.1186/s12967-023-03875-4 · Cited by 20
“As reported in previous studies, mitogen-activated protein kinase kinase (MEK) and cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors could directly alter immune cell function and contribute to antitumor immunity synergized with PD-L1 blockade [13, 14].”
Valenza, C., Rizzo, G., Passalacqua, M. I., Boldrini, L., Corti, C., Trapani, D., & Curigliano, G. (2023) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359221146129 · Cited by 23
Engineering Heterogeneous Tumor Models for Biomedical Applications
Wu, Z., Huang, D., Wang, J., Zhao, Y., Sun, W., & Shen, X. (2023) · Advanced Science · doi:10.1002/advs.202304160 · Cited by 19
Effect of CDK4/6 Inhibitors on Tumor Immune Microenvironment
Liu, J., Cheng, M., Xu, J., Liang, Y., Yin, B., & Liang, J. (2024) · Immunological Investigations · doi:10.1080/08820139.2024.2304565 · Cited by 20
“The activated T cells and the induction of antitumor immunity would be enhanced by the abemaciclib therapy, which significantly elevates the expression of genes related to T cell function and activation (Deng et al., 2018; Schaer et al., 2018).”
BackgroundInfluentialMagrath, J. W., Espinosa-Cotton, M. M., Flinchum, D. A., Sampath, S. S., Cheung, N. V., & Lee, S. B. (2024) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2024.1442488 · Cited by 23
Odan, N., Kikawa, Y., Matsumoto, H., Minohata, J., Suwa, H., Hashimoto, T., Okuno, T., Miyashita, M., Saito, M., Yamagami, K., et al. (2020) · Breast Cancer Basic and Clinical Research · doi:10.1177/1178223420983843 · Cited by 20
Chen, D., Xu, L., Xuan, M., Chu, Q., & Xue, C. (2024) · Clinical and Translational Medicine · doi:10.1002/ctm2.1802 · Cited by 20
“78 However, they lack the complex tissue architecture found in organoids.”
BackgroundWang, X., Zhong, L., & Zhao, Y. (2021) · Oncology Reports · doi:10.3892/or.2021.8000 · Cited by 21
“Immune checkpoint molecules are predominantly inhibitory molecules, in which the immune checkpoint on T cells suppresses the immune function of T cells, causing tumor escape (103).”
BackgroundEmile, G., Penager, S., Lévy, C., Johnson, A., Allouache, D., Lequesne, J., Hrab, I., Ségura, C., Morel, A., Gunzer, K., et al. (2021) · Oncology Letters · doi:10.3892/ol.2021.13143 · Cited by 19
“Finally, CDK4/6i may decrease the proliferation of regulatory TL (32,36), reversing the balance of TL effectors and TL regulators in favor of tumor control.”
BackgroundBiggi, A. F. B., & de Oliveira, D. E. (2022) · Biomolecules · doi:10.3390/biom12030397 · Cited by 22
“In this context, treating tumors with CDK4/6 inhibitors greatly enhances the effects of anti-PD-1 therapy [91,92].”
BackgroundTargeting micro-environmental pathways by PROTACs as a therapeutic strategy
Liu, J., Peng, Y., Inuzuka, H., & Wei, W. (2022) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2022.07.001 · Cited by 20
Liu, Y., Chen, X., Luo, W., Zhao, Y., Nashan, B., Huang, L., & Yuan, X. (2023) · Cancer Medicine · doi:10.1002/cam4.6271 · Cited by 18
Hermida‐Prado, F., Xie, Y., Sherman, S., Nagy, Z., Russo, D., Akhshi, T. K., Chu, Z., Feit, A. S., Campisi, M., Chen, M., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-23-1711 · Cited by 19
“Previous studies demonstrated that CDK4/6i can increase the immunogenicity and response to ICIs in models of breast cancer and other cancer types by in fl uencing the tumor cells and TME through several mechanisms (55, 56).”
Self-citationEstablishing mouse and human oral esophageal organoids to investigate the tumor immune response
Jiang, Y., Zhao, H., Kong, S., Zhou, D., Dong, J., Cheng, Y., Zhang, S., Wang, F., Kalra, A., Yang, N., et al. (2024) · Disease Models & Mechanisms · doi:10.1242/dmm.050319 · Cited by 19
“These studies have shown upregulated expression of cytotoxic proteins and secretion of cytokines, as well as intratumoral immune cell reinvigoration upon the treatment of ICB (Jenkins et al., 2018; Neal et al., 2018; Voabil et al., 2021).”
InfluentialSelf-citationCDK4/6 Alters TBK1 Phosphorylation to Inhibit the STING Signaling Pathway in Prostate Cancer
Li, W., Guo, F., Zeng, R., Liang, H., Wang, Y., Xiong, W., Wu, H., Yang, C., & Jin, X. (2024) · Cancer Research · doi:10.1158/0008-5472.can-23-3704 · Cited by 19
Oppelt, P., Ley, J. C., Worden, F. P., Palka, K. A., Maggiore, R. J., Liu, J., & Adkins, D. R. (2021) · Oral Oncology · doi:10.1016/j.oraloncology.2020.105164 · Cited by 18
Foffano, L., Cucciniello, L., Nicolò, E., Migliaccio, I., Noto, C., Reduzzi, C., Malorni, L., Cristofanilli, M., Gerratana, L., & Puglisi, F. (2024) · The Breast · doi:10.1016/j.breast.2024.103863 · Cited by 19
“Effects on cytokines have also been described, including an increase in the pro-inflammatory chemokines CXCL9, CXCL10 and CCL5 and a reduction in IL6, IL10, and IL23 levels and coinhibitory molecules, such as PD-1 and CTLA4 [120].”
T Cell-Intrinsic CDK6 Is Dispensable for Anti-Viral and Anti-Tumor Responses In Vivo
Klein, K., Witalisz‐Siepracka, A., Gotthardt, D., Agerer, B., Sternberg, F., Grausenburger, R., Knab, V. M., Bergthaler, A., & Sexl, V. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.650977 · Cited by 19
“org 14 particularly sensitive to CDK4/6 inhibitor treatment (24, 25, 68).”
BackgroundResultInfluentialEngineering the Immune Microenvironment into Organoid Models
Luckett, K. A., & Ganesh, K. (2023) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-061421-040659 · Cited by 20
Rottier, P., Silva, A. D., Johnson, A. C., Lévy, C., Allouache, D., Hrab, I., Ségura, C., Morel, A., Villemin, M., Boscher, C., et al. (2023) · Frontiers in Oncology · doi:10.3389/fonc.2022.1105587 · Cited by 17
“Median age was 65 years [29-86], 40% patients had good performance status (ECOG-PS 0).”
BackgroundTackling of Immunorefractory Tumors by Targeting Alternative Immune Checkpoints
Dulal, D., Boring, A. R., Terrero, D., Johnson, T. L., Tiwari, A. K., & Raman, D. (2023) · Cancers · doi:10.3390/cancers15102774 · Cited by 20
Microphysiological Systems for Cancer Immunotherapy Research and Development
Peng, Y., & Lee, E. (2023) · Advanced Biology · doi:10.1002/adbi.202300077 · Cited by 17
Wang, L., Wu, Y., Kang, K., Zhang, X., Luo, R., Tu, Z., Zheng, Y., Guo, L., Wang, H., Tang, M., et al. (2024) · Translational Lung Cancer Research · doi:10.21037/tlcr-24-33 · Cited by 18
Strategy of combining CDK4/6 inhibitors with other therapies and mechanisms of resistance
Xue, Y. (2024) · International Journal of Clinical and Experimental Pathology · doi:10.62347/hgni4903 · Cited by 18
Cyclin-Dependent Kinase Inhibition in Prostate Cancer: Past, Present, and Future
Siskin, M., Economides, M. P., & Wise, D. R. (2025) · Cancers · doi:10.3390/cancers17050774 · Cited by 22
“Of note, prolonged CDK4/6 inhibition has been noted to be immunosuppressive in animal models, prompting some authors to propose that properly timed short-term CDK4/6 treat-ment could potentiate immune checkpoint therapy [94].”
Luo, C., Hou, M., Huang, C., Wu, C., Ou‐Yang, F., Li, Q.-L., Wu, C.-C., & Pan, M. (2020) · PubMed Central · Cited by 18
Battaglia, A. M., Sacco, A., Aversa, I., Santamaria, G., Palmieri, C., Botta, C., Stefano, R. D., Bitetto, M., Petriaggi, L., Giorgio, E., et al. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1208485 · Cited by 17
Bozym, D. J., Zheng, D. X., Revach, O., Aref, A. R., & Jenkins, R. W. (2025) · Lab on a Chip · doi:10.1039/d5lc00062a · Cited by 20
Self-citationA review of immune checkpoint blockade in breast cancer
Pellegrino, B., Tommasi, C., Cursio, O. E., Musolino, A., Migliori, E., Silva, P. D., Senevirathne, T. H., Schena, M., Scartozzi, M., Farci, D., et al. (2021) · Seminars in Oncology · doi:10.1053/j.seminoncol.2021.09.002 · Cited by 17
Visani, L., Livi, L., Ratoša, I., Oražem, M., Ribnikar, D., Saieva, C., Becherini, C., Salvestrini, V., Scoccimarro, E., Valzano, M., et al. (2022) · Radiotherapy and Oncology · doi:10.1016/j.radonc.2022.10.023 · Cited by 17
Evolving perspectives on the treatment of HR+/HER2+ metastatic breast cancer
Pegram, M. D., Pietras, R. J., Dang, C. T., Murthy, R. K., Bachelot, T., Janni, W., Sharma, P., Hamilton, E. P., & Saura, C. (2023) · Therapeutic Advances in Medical Oncology · doi:10.1177/17588359231187201 · Cited by 20
Cathepsin V is correlated with the prognosis and tumor microenvironment in liver cancer
Liu, J., Zhang, W., Wang, Z., Wang, Y., Li, T., Wang, Y., Ding, J., & Ning, B. (2023) · Molecular Carcinogenesis · doi:10.1002/mc.23660 · Cited by 17
Drugs in development for small cell lung cancer
Serzan, M. T., Farid, S., & Liu, S. V. (2020) · Journal of Thoracic Disease · doi:10.21037/jtd-2019-sclc-10 · Cited by 17
“Preclinical studies have also analyzed the effect of CDK 4/6 inhibition on immune cell function (31).”
BackgroundDesign and pharmaceutical applications of proteolysis-targeting chimeric molecules
Liang, Y., Nandakumar, K. S., & Cheng, K. (2020) · Biochemical Pharmacology · doi:10.1016/j.bcp.2020.114211 · Cited by 16
Mitosis in Cancer Cell Increases Immune Resistance via High Expression of HLA-G and PD-L1
Ullah, M., Aoudjeghout, W., Pimpie, C., Pocard, M. D., & Mirshahi, M. (2020) · Cancers · doi:10.3390/cancers12092661 · Cited by 18
“It has been reported that selective CDK4/6 pharmacologically enhances the tumor infiltration by immune cells [10,11].”
BackgroundResulthttps://cdrjournal.com/article/view/3531
Moreira, M., Pobel, C., Epaillard, N., Simonaggio, A., Oudard, S. M., & Vano, Y. A. (2020) · Cancer Drug Resistance · doi:10.20517/cdr.2020.16 · Cited by 20
“Greater IL-2 production and increased T cell tumor infiltration were observed([57]).”
BackgroundClinical Data on Immunotherapy in Breast Cancer
Radosa, J. C., Stotz, L., Müller, C., Kaya, A. C., Solomayer, E., & Radosa, M. P. (2020) · Breast Care · doi:10.1159/000511788 · Cited by 19
Balko, J. M., & Sosman, J. A. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-17-1356 · Cited by 17
“In the second report, by Deng and colleagues, the PDOT/ MDOT systems were also used in support of the beneficial effects of CDK4/6 inhibition on tumor immunity (5).”
BackgroundMethodHe, F., Zhang, Q., Chen, Y., Ge, S., Xie, Y., Sun, R., Wu, Y., & Xu, J. (2025) · International Journal of Molecular Medicine · doi:10.3892/ijmm.2025.5564 · Cited by 18
“The combination of CDK4/6 inhibitors and RT has been shown to induce a higher proportion of cells to remain in the G 2 /M phase of the cell cycle (1,32,210,213,214).”
Redirecting the Neo-Substrate Specificity of Cereblon-Targeting PROTACs to Helios
Verano, A. L., You, I., Donovan, K. A., Mageed, N., Yue, H., Nowak, R. P., Fischer, E. S., Wang, E. S., & Gray, N. S. (2022) · ACS Chemical Biology · doi:10.1021/acschembio.2c00439 · Cited by 16
Self-citationCDK4/6 Inhibitors in Pancreatobiliary Cancers: Opportunities and Challenges
Arsenijevic, T., Coulonval, K., Raspé, E., Demols, A., Roger, P. P., & Laethem, J. V. (2023) · Cancers · doi:10.3390/cancers15030968 · Cited by 18
“Senescent cells acquire a pro-inflammatory senescence-associated secretory phenotype (SASP) that leads to their elimination mediated by macrophages and CD4+ T-cells [115].”
BackgroundMoukas, S. I., Kasimir‐Bauer, S., Tewes, M., Kolberg, H., Hoffmann, O., Kimmig, R., & Keup, C. (2023) · Scientific Reports · doi:10.1038/s41598-023-47874-3 · Cited by 17
CDK4/RB/E2Fs axis as potential therapeutic target of endometrial cancer
Hu, J., Shen, J., & Sun, J. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.109870 · Cited by 18
Ledys, F., Kalfeist, L., Galland, L., Limagne, E., & Ladoire, S. (2021) · Cancers · doi:10.3390/cancers13235999 · Cited by 18
Zhang, S., Xu, L., Feng, J., Tan, D., Zhu, Y., Hou, J., Li, W., Lv, K., Wang, W., Jiang, L., et al. (2022) · Frontiers in Genetics · doi:10.3389/fgene.2022.842351 · Cited by 18
F-box protein FBXO32 ubiquitinates and stabilizes D-type cyclins to drive cancer progression
Li, F., Yu, H., Zhang, Y., Ma, Y., Chen, X., Zhang, J., Sun, L., Guo, R., Wu, Y., Zheng, P., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-59407-9 · Cited by 18
Self-citationJurj, A. M., Paşca, S., Braicu, C., Rusu, I., Korban, S. S., & Berindan‐Neagoe, I. (2021) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2021.12.002 · Cited by 15
Zhang, W., Shang, X., Yang, F., Han, W., Xia, H., Liu, G., Liu, Y., & Wang, X. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.867788 · Cited by 15
Barghi, F., Shannon, H. E., Saadatzadeh, M. R., Bailey, B. J., Riyahi, N., Bijangi‐Vishehsaraei, K., Just, M., Ferguson, M. J., Pandya, P. H., & Pollok, K. E. (2022) · Cancers · doi:10.3390/cancers14153611 · Cited by 15
“For example, CDK4/6 inhibition increased IL-2 and CD4+ T-cell activation [113] and blocked the growth of immunosuppressive regulatory T cells [114].”
BackgroundLiu, Y., & Jiao, A. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1703672 · Cited by 19
Qiu, J., Sheng, D., Lin, F., Jiang, P., & Shi, N. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1157251 · Cited by 14
Khorrami, M., Viswanathan, V. S., Reddy, P., Braman, N. M., Kunte, S., Gupta, A. B., Abraham, J., Montero, A. J., & Madabhushi, A. (2023) · npj Breast Cancer · doi:10.1038/s41523-023-00574-7 · Cited by 14
“It can be postulated that peri-tumoral Gabor texture increase during therapy might be capturing the presence of immune T-cells around the tumor, caused by CDK4/6i therapy and might be an indicator of better response to therapy.”
Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints
Cannon, A. C., Budagyan, K., Uribe‐Alvarez, C., Kurimchak, A., Araiza‐Olivera, D., Cai, K. Q., Peri, S., Zhou, Y., Duncan, J. S., & Chernoff, J. (2024) · Oncogene · doi:10.1038/s41388-024-02947-z · Cited by 15
Wei, X., Yang, M. W., Zou, H., Shen, S., Li, Y., Chen, L., Liu, Y., Li, D., & Ding, J. (2025) · Journal of Controlled Release · doi:10.1016/j.jconrel.2025.02.020 · Cited by 14
Short- and Long-Term Effects of CDK4/6 Inhibition on Early-Stage Breast Cancer
Kietzman, W. B., Graham, G. T., Ory, V., Sharif, G. M., Kushner, M. H., Gallanis, G. T., Kallakury, B., Wellstein, A., & Riegel, A. T. (2019) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-19-0231 · Cited by 14
Decoding Novel Mechanisms and Emerging Therapeutic Strategies in Breast Cancer Resistance
Shafi, S., Khan, S. I., Hoda, F., Fayaz, F., Singh, A., Khan, M. A., Ali, R., Pottoo, F. H., Tariq, S., & Najmi, A. K. (2020) · Current Drug Metabolism · doi:10.2174/1389200221666200303124946 · Cited by 14
Anti-cancer therapy with cyclin-dependent kinase inhibitors: impact and challenges
Reinius, M., & Smyth, E. C. (2021) · Expert Reviews in Molecular Medicine · doi:10.1017/erm.2021.3 · Cited by 14
Lin, Y., Wang, Y., Yeh, D.-W., Hung, C.-Y., Yeh, Y., Ho, H., Mon, H.-C., Chen, M., Wu, Y., & Chou, T. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413374 · Cited by 14
“In a mouse non-small-cell lung-cancer model, the inhibition of CDK4/6, the downstream target of p16, resulted in increased CD4 and CD8 T cell infiltration in the tumor [23].”
BackgroundModulation of Type I Interferon Responses to Influence Tumor-Immune Cross Talk in PDAC
Cattolico, C., Bailey, P., & Barry, S. T. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.816517 · Cited by 17
“, 2018) and syngeneic models (Deng et al., 2018) to treatment.”
BackgroundMavratzas, A., & Marmé, F. (2021) · Breast Care · doi:10.1159/000514561 · Cited by 14
Chen, D., Wang, B., Li, C., Tao, H., Lu, F., Ruan, Z., Zhao, Z., Li, C., Yan, G., Zhang, H., et al. (2025) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102239 · Cited by 19
Self-citationTargeting cyclin-dependent kinase 4/6 as a therapeutic approach for mucosal melanoma
Shi, C.-J., Xu, S.-M., Han, Y., Zhou, R., & Zhang, Z.-Y. (2021) · Melanoma Research · doi:10.1097/cmr.0000000000000777 · Cited by 13
Sourcing cells for in vitro models of human vascular barriers of inflammation
McCloskey, M. C., Zhang, V. Z., Ahmad, S. D., Walker, S. N., Romanick, S., Awad, H. A., & McGrath, J. L. (2022) · Frontiers in Medical Technology · doi:10.3389/fmedt.2022.979768 · Cited by 13
Organoids as an Enabler of Precision Immuno-Oncology
Zhao, J., Fong, A. S. W., Seow, S. V., & Toh, H. C. (2023) · Cells · doi:10.3390/cells12081165 · Cited by 13
“MOSs [43], PDOTS [44], ALI [45], and TSCs [46,59] have all recapitulated the anti-PD-1 response ex vivo, with the potential to test novel therapeutic combinations such as ICIs + CDK4/6 inhibitors [47].”
BackgroundResultXie, D., Jiang, B., Wang, S., Wang, Q., & Wu, G. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1200466 · Cited by 15
Drug Repurposing to Circumvent Immune Checkpoint Inhibitor Resistance in Cancer Immunotherapy
To, K. K. W., & Cho, W. C. S. (2023) · Pharmaceutics · doi:10.3390/pharmaceutics15082166 · Cited by 16
“Moreover, CDK4/6 inhibitors were also found to diminish Treg proliferation and enhance the effector T cell activity by downregulating the nuclear factor of activated T cells (NFAT, which regulates Treg transcription) [106].”
BackgroundDUX4 is a common driver of immune evasion and immunotherapy failure in metastatic cancers
Pineda, J. M. B., & Bradley, R. K. (2023) · eLife · doi:10.7554/elife.89017 · Cited by 15
“…in reduced ICI efficacy, and combination treatment with an MAPK/CDK inhibitor improves response to checkpoint blockade ( Ascierto et al., 2019 ; Deng et al., 2018 ; Ebert et al., 2016 ; Goel et al., 2017 ; Jerby-Arnon et al., 2018 ; Ribas et al., 2019 ; Schaer et al., 2018 ; Sullivan et al.,…”
BackgroundApplication of organoids in precision immunotherapy of lung cancer (Review)
Tian, H., Ren, J., Mou, R., & Jia, Y. (2023) · Oncology Letters · doi:10.3892/ol.2023.14071 · Cited by 14
Progress, application and challenges of liver organoids
Sang, C., Lin, J., Ji, S., & Gao, Q. (2024) · Clinical Cancer Bulletin · doi:10.1007/s44272-024-00012-0 · Cited by 14
“In recent years, several studies have successfully constructed tumor immune organoids systems by Holistic or Reductionist methods [129–131].”
Wang, Y., Wang, X., Li, W., Huang, H., Di, C., & Yang, Q. (2025) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2025.119723 · Cited by 13
Cell Cycle Dysregulation in Mantle Cell Lymphoma
Wang, K., Huang, X., Liberto, M. D., & Chen‐Kiang, S. (2020) · Hematology/Oncology Clinics of North America · doi:10.1016/j.hoc.2020.05.003 · Cited by 12
Metadata
- Authors
- Deng, J., Wang, E. S., Jenkins, R. W., Li, S., Dries, R., Yates, K., Chhabra, S., Huang, W., Liu, H., Aref, A. R., Ivanova, E., Paweletz, C. P., Bowden, M., Zhou, C. W., Herter-Sprie, G. S., Sorrentino, J. A., Bisi, J. E., Lizotte, P. H., Merlino, A. A., Quinn, M. M., Bufe, L. E., Yang, A., Zhang, Y., Zhang, H., Gao, P., Chen, T., Cavanaugh, M. E., Rode, A. J., Haines, E., Roberts, P. J., Strum, J. C., Richards, W. G., Lorch, J. H., Parangi, S., Gunda, V., Boland, G. M., Bueno, R., Palakurthi, S., Freeman, G. J., Ritz, J., Haining, W. N., Sharpless, N. E., Arthanari, H., Shapiro, G. I., Barbie, D. A., Gray, N. S., & Wong, K.-K.
- Affiliations
- NYU Langone Health (US)
- Harvard University (US)
- Dana-Farber Cancer Institute (US)
- 9G1 Therapeutics, Research Triangle Park, North Carolina.
- Brigham and Women's Hospital (US)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Barbie, David A.
- Gray, Nathanael S.
- Wong, Kwok-Kin
- ORCID
- Deng, Jiehui
- Wang, Eric S.
- Jenkins, Russell W.
- Li, Shuai
- Dries, Ruben
- Yates, Kathleen
- Chhabra, Sandeep
- Huang, Wei
- Liu, Hongye
- Aref, Amir R.
- Ivanova, Elena
- Paweletz, Cloud P.
- Bowden, Michaela
- Zhou, Chensheng W.
- Herter-Sprie, Grit S.
- Sorrentino, Jessica A.
- Bisi, John E.
- Lizotte, Patrick H.
- Yang, Annan
- Zhang, Hua
- Gao, Peng
- Chen, Ting
- Haines, Eric
- Roberts, Patrick J.
- Strum, Jay C.
- Richards, William G.
- Lorch, Jochen H.
- Parangi, Sareh
- Boland, Genevieve M.
- Bueno, Raphael
- Palakurthi, Sangeetha
- Freeman, Gordon J.
- Ritz, Jerome
- Haining, W. Nicholas
- Sharpless, Norman E.
- Arthanari, Haribabu
- Shapiro, Geoffrey I.
- Barbie, David A.
- Gray, Nathanael S.
- Wong, Kwok-Kin
- Venue
- Cancer Discovery
- Published
- 2018-02-01
- Volume
- 8
- Issue
- 2
- Pages
- 216-233
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC5809273
- OpenAlex
- W2766016994
- Cited by
- 770
- References
- 63
- Citations by year
- 2026: 62 · 2025: 111 · 2024: 83 · 2023: 109 · 2022: 115 · 2021: 104 · 2020: 96 · 2019: 61 · 2018: 29
- FWCI
- 22.43
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Damon Runyon Cancer Research Foundation (Damon Runyon) (DRG-2270-16)
- HHS | NIH | National Cancer Institute (NCI) (CA154303-05, CA179483-03, P01CA120964, 5R01CA163896-04, 5R01CA140594-07, 5R01CA122794-10, 5R01CA166480-04)
- Dana-Farber Cancer Institute (DFCI) (Medical Oncology Discovery Grant)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Signaling Pathways in Disease
- Keywords
- CDK4/6 inhibitors, antitumor immunity, T cell activation, anti-PD-1 therapy, immune checkpoint blockade, combination immunotherapy, tumor-infiltrating T cells, small-molecule immunomodulators
- MeSH terms
- Antineoplastic Agents, Immunological, Animals, Antineoplastic Agents, Humans, Lymphocyte Activation, Neoplasms, T-Lymphocytes, Lymphocytes, Tumor-Infiltrating, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
