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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
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“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]
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BackgroundMethodInfluential
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BackgroundCarbon ion irradiation mobilizes antitumor immunity: from concept to the clinic
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“For example, inhibition of CDK4/6 expressed in T cells enhances T cell activation to augment anti-tumor immunity by increasing IL-2 secretion, which in turn largely improves the clinical benefits of combined CDK4/6 inhibitors and immunotherapy approaches.(33,34) In line with these findings, our data pinpointed that th…”
ResultThe roles of cell cycle proteins in regulating the tumor immune microenvironment
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InfluentialSelf-citationDevelopment of CDK4/6 Inhibitors in Gastrointestinal Cancers: Biomarkers to Move Forward
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BackgroundCDK4/6 Inhibitor Resistance in ER+ Breast Cancer
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CDK4/6 inhibition protects normal cells against cancer therapy-induced damage
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BackgroundPrecision and Immunoprevention Strategies for Tobacco-Related Head and Neck Cancer Chemoprevention
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“Additionally, the immunomodulatory effects of CDK4 and CDK6 present complex challenges for the targeted therapy of these kinases [25].”
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“Additionally, they are capable of activating effector T-cells and boost the infiltration of B-lymphocytes and natural killer (NK) cells [15].”
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“Moreover, CDK4/6 inhibitors have been shown to enhance antitumor immunity by promoting the infiltration of effector T cells into tumors [21] and upregulating immune-related markers such as PD-L1 [22].”
Recent Developments in Cyclin-Dependent Kinase (CDK) PROTAC in Cancer Therapy
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“Given the role of NFAT in IL-2-mediated T cell activation, its inhibition by CDK6 impairs effector T cell’s function [76].”
D’Angelo, A., Giudici, F., Chapman, R., Darlow, J., Kilili, H., Sobhani, N., Cinelli, M., Cappelletti, M. R., Strina, C., Milani, M., et al. (2022) · Current Issues in Molecular Biology · doi:10.3390/cimb44090292 · Cited by 3
“On the contrary, CDK4/6 i can enable cytotoxic activity by mitigation of myeloid-cell-mediated immunosuppression [43].”
BackgroundCeylan, F., Mehdiyev, M., Dede, D. Ş., Efil, S. C., Tenekeci, A. K., Bi̇lgi̇n, B., Yücel, Ş., Doğan, H. T., Şendur, M. A. N., Akıncı, M. B., et al. (2024) · Journal of Clinical Medicine · doi:10.3390/jcm14010173 · Cited by 3
“This dual effect suggests a complex dynamic where CDK4/6 inhibitors may enhance the immune recognition of tumor cells but limit the expansion of T cell populations, potentially influencing the overall effectiveness of immune responses during treatment [35].”
Markowitz, M. E., Barak-Levitt, J., Merose, R., Didkovski, E., Snast, I., Oren‐Shabtai, M., Barzilai, A., Mimouni, D., & Sherman, S. (2025) · Clinical and Experimental Dermatology · doi:10.1093/ced/llaf123 · Cited by 3
Zhang, Y., Xu, Y., Zhang, Y., Wang, S., & Zhao, M. (2025) · Frontiers in Pharmacology · doi:10.3389/fphar.2025.1559408 · Cited by 3
“For instance, lncRNAs not only exert in fl uence over tumor cells through cyclins but also play a signi fi cant role in modulating the TME (Deng et al., 2018; Goel et al., 2017).”
InfluentialSelf-citationZhang, Y., Sun, B., Zhou, R., Gong, Z., Han, Y., Tao, W., Shi, C., Zhang, W., Liu, L., Zhang, Z., et al. (2025) · Advanced Science · doi:10.1002/advs.202510501 · Cited by 3
Self-citationA Review on Patient-derived 3D Micro Cancer Approach for Drug Screen in Personalized Cancer Medicine
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Feng, Z., Qin, M., Jiang, J., Wang, M., Zhang, T., Li, Y., Liu, X., Zhang, J., Shi, H., Zhao, Y., et al. (2025) · Nano Letters · doi:10.1021/acs.nanolett.4c06018 · Cited by 3
Saavedra, C., Vallejo, A., Longo, F., Domingo, J. J. S., Fernández-Abad, M., Gión, M., López-Miranda, E., Martínez-Jáñez, N., Guerra, E. M., Chamorro, J., et al. (2023) · Cancers · doi:10.3390/cancers15072000 · Cited by 3
“On the contrary, preclinical data suggest that CDK4/6i could boost immunity due to the involvement of the CDK complexes in the development and activation of the immune system [14,15].”
BackgroundWhen Molecular-Targeted Agents Meet Immunotherapy: The Opportunities for Soft Tissue Sarcoma
Wainsztein, V., & Chen, T. W. (2020) · Journal of Immunotherapy and Precision Oncology · doi:10.36401/jipo-19-37 · Cited by 3
Self-citationDrugs repurposed to potentiate immunotherapy for cancer treatment
To, K. K. W., & Cho, Y. (2020) · Elsevier eBooks · doi:10.1016/b978-0-12-819668-7.00012-9 · Cited by 3
Estrogen receptor positive breast cancer patient–derived xenograft models in translational research
Chia, K., Freelander, A., Kumar, S. S., Parker, A., Segara, D., Portman, N., & Lim, E. (2020) · Current Opinion in Endocrine and Metabolic Research · doi:10.1016/j.coemr.2020.10.004 · Cited by 3
Agahozo, M. C., Smid, M., van Marion, R., Hammerl, D., van den Bosch, T. P. P., Timmermans, M. A. M., Heijerman, C. J., Westenend, P. J., Debets, R., Martens, J. W. M., et al. (2021) · Biology · doi:10.3390/biology10080768 · Cited by 3
“Additionally, inhibiting these kinases increased T cell infiltration and activation of effector T cells in (murine) tumors [65,66].”
BackgroundGriffiths, J. I., Cosgrove, P. A., Castaneda, E. M., Nath, A., Chen, J., Adler, F. R., Chang, J. T., Khan, Q. J., & Bild, A. H. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.14.507931 · Cited by 4
Reviving p18INK4c: Harnessing a tumor suppressor for cancer treatment
Jerka, D., Bonowicz, K., Bai, Y., Reiter, R. J., Żuryń, A., & Gagat, M. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152674 · Cited by 2
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Self-citationAhmadi, R., Sadeghi, K. F., Sharmsar, O., Bagheri, Y., Sadeghi, K. F., Koochehloghmani, H., & Hoseinpourfeyzi, M. (2025) · Critical Reviews in Oncology/Hematology · doi:10.1016/j.critrevonc.2025.104989 · Cited by 3
Markowitz, M. E., Merose, R., Didkovski, E., Doron, A., Iton-Schwartz, A., Shitrit, S. B., Barzilai, A., Gal‐Yam, E. N., Kidron, D., Sonnenblick, A., et al. (2025) · Clinical and Experimental Dermatology · doi:10.1093/ced/llaf482 · Cited by 2
Zhu, R., Zhang, H., & Zhang, F. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1693927 · Cited by 3
“Additionally, in immune-reconstituted xenograft models, combined PI3K a and CDK4/6 inhibition has been associated with remodeling of the tumor immune microenvironment, including increased CD8+ T cell in fi ltration and enhanced cytotoxic effector markers (such as Granzyme B) (56, 68, 69).”
Self-citationPapagiannis, A., Majjaj, S., Duhoux, F. P., Agostinetto, E., Stanciu, A., Vanhulst, T., Buisseret, L., Larsimont, D., Veys, I., Paesmans, M., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-66590-2 · Cited by 2
“In addition, CDK4/6inhibitors,includingpalbociclib,havebeenshowntoaugment T cell activation and increase T cell in fi ltration in murine lung tumors 17 .”
Immune Checkpoint Inhibitor Therapy in Hormone Receptor-Positive Breast Cancer
Lin, D. W., Lee, J. S., Ma, I., & Yuan, Y. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms262412171 · Cited by 2
“In addition, several pre-clinical tests, including a novel ex vivo organotypic tumor spheroid culture system and multiple in vivo murine syngeneic models, has shown that CDK4/6 inhibition augments the response to PD-1 blockade, thereby providing a rationale for combining CDK4/6i and ICI [31].”
Babatunde, O. O., Seier, K., Schwartz, G. K., Keohan, M. L., D’Angelo, S. P., Gounder, M. M., Chi, P., Antonescu, C. R., Landa, J., Qin, L.-X., et al. (2026) · ESMO Open · doi:10.1016/j.esmoop.2026.106899 · Cited by 2
“23,24 This combination is currently being evaluated in an ongoing clinical trial (NCT04438824), with early results indicating promising responses in a subset of patients.”
Xie, M., Yang, F., Zhu, S., Xu, Y., & Li, X. (2026) · Naunyn-Schmiedeberg s Archives of Pharmacology · doi:10.1007/s00210-026-05230-y · Cited by 2
“At pre-sent, the precise underlying mechanisms remain to be fully elucidated (Deng et al. 2018; Desai et al. 2013).”
Strawser, C., Chakraborty, B., Michaud, D. E., Chang, C., Dent, S., Jain, V., Tolaney, S. M., Weinhold, K. J., McAllister, S. S., Miller, K. E., et al. (2026) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-25-0946 · Cited by 2
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Self-citationChen, L., Liu, Y., Zhu, N., Xie, H., Zhu, T., Duan, Q., Zhang, L., Liu, Z., Zhou, X. Y., & Tong, J. (2026) · APOPTOSIS · doi:10.1007/s10495-026-02381-4 · Cited by 2
“These findings demonstrated that Palbociclib promotes macrophage polarization toward the M1 phenotype by targeting p53, through reducing p53 mRNA levels and inducing its protein degradation.”
Yang, Y., Zhu, S., Fu, Z., Sun, C., Yang, F., Zeng, T., Hua, Y., Bao, S., Gao, X., Huang, X., et al. (2021) · Translational Breast Cancer Research · doi:10.21037/tbcr-20-54 · Cited by 1
“Also, CDK 4/6 inhibitors increase the infiltration of tumor cells and activate effector T cells via de-repression of the nuclear factor of activated T cell (NFAT) proteins, which synergize with immunotherapies (81).”
BackgroundMolecular Subtypes of Breast Cancer and CDk Dysregulation
Mir, M. A., & Din, I. M. U. (2023) · Springer eBooks · doi:10.1007/978-981-19-8911-7_6 · Cited by 2
Hossain, M. A., Ahsan, A., Hasan, I., Sohel, Khan, A. A., Somadder, P. D., Monjur, S., Miah, S., Kibria, K. M. K., Ahmed, K., et al. (2024) · The International Journal of Biological Markers · doi:10.1177/03936155241230968 · Cited by 2
“39 Anti-melanoma immune checkpoint drugs can slow tumor development by decreasing CDK4/ 6 activity, slowing the resistance pathway, and inducing senescence.”
BackgroundPotential role of cyclin-dependent kinase 4/6 inhibitors in the treatment of mucosal melanoma
Shi, C., Ju, H., Wu, Y., Ma, X., Zhang, Z., & Ren, G. (2024) · Holistic Integrative Oncology · doi:10.1007/s44178-024-00090-z · Cited by 3
“It has been demonstrated in preclinical models that selective CDK4/6 inhibitors induce tumor cell cycle arrest and enhance immune-mediated antitumor responses [68, 71, 110].”
InfluentialIntegrating cuproptosis and immunosenescence: A novel therapeutic strategy in cancer treatment
Firouzjaei, A. A., & Aghaee‐Bakhtiari, S. H. (2025) · Biochemistry and Biophysics Reports · doi:10.1016/j.bbrep.2025.101983 · Cited by 4
“These findings indicate that combining CDK4/6 inhibitors with PD-L1 blockade could enhance the effectiveness of immunotherapy in cancer patients [162].”
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Ma, S., Hu, R., Xue, X., Qu, M., & Sun, G. (2025) · Oncology Letters · doi:10.3892/ol.2025.15170 · Cited by 2
“Stimulating effector T‑lymphocyte activation and reducing the proliferation of immunosuppressive cells are the primary mechanisms of action for other targeted therapy medications (53,54).”
Hao, W., Liu, S., Qin, Y., Sun, C., Bao, J., & Wu, C. (2025) · Oncology Letters · doi:10.3892/ol.2025.15251 · Cited by 2
“Abemaciclib exerts potent inhibitory activity against CDK4/6, leading to hypophosphorylation of the retinoblastoma protein, sustained E2F transcription factor suppression and resultant G1‑phase cell cycle arrest in lymphocytes (15).”
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Opportunities for Antigen Discovery in Metastatic Breast Cancer
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Novel CDK Inhibitors in Breast Cancer
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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
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