# γδ T cells and resistance to CDK4/6 inhibitors in breast cancer

Oliver Kepp, Guido Kroemer

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## To cite this version:

Oliver Kepp, Guido Kroemer. γδ T cells and resistance to CDK4/6 inhibitors in breast cancer. Cell Death and Disease, 2025, 16 (1), pp.830. 10.1038/s41419-025-08149-z. hal-05383969

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Submitted on 26 Nov 2025

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# γδ T cells and resistance to CDK4/6 inhibitors in breast cancer

© The Author(s) 2025

Cell Death and Disease (2025)16:830; https://doi.org/10.1038/s41419-025-08149-z

Endocrine therapy remains the cornerstone for the treatment of advanced and metastatic hormone-receptor-positive, HER2-negative (HR+/HER2+) breast cancer. The introduction of cyclin-dependent kinase-4/6 (CDK4/6) inhibitors, palbociclib, ribociclib, and abemaciclib, into clinical practice, has enhanced the clinical benefit of endocrine therapy through the inhibition of retino-blastoma (RB) phosphorylation. This has translated into prolonged progression-free intervals and overall survival [1–3].

Nevertheless, therapeutic pressure inevitably drives the emergence of resistance, limiting the durability of responses. While CDK4/6 inhibitors are best known for their cytostatic activity, increasing evidence suggests they also modulate tumor immunity. These agents can induce a senescence-associated secretory phenotype (SASP), enhance antigen presentation, and selectively deplete regulatory T cells [4, 5]. These immunostimulatory effects have provided a rationale for combining CDK4/6 inhibition with immune-checkpoint blockade in clinical trials.

Paradoxically, however, recent findings suggest that CDK4/6 inhibition can also activate compensatory immunosuppressive circuits within the tumor microenvironment, potentially under-mining long-term therapeutic efficacy. Petroni et al., using murine models of HR+/HER2+ breast cancer, demonstrated that the combination of palbociclib and endocrine therapy provokes a hypoxia-sensitive, chemokine (C-C motif) ligand 2 (CCL2)-mediated influx of interleukin-17A (IL-17A)-secreting γδ T cells.

These γδ T lymphocytes reprogram tumor-associated macrophages towards a CX3C motif chemokine receptor 1-positive (CX3CR1+) state characterized by reduced antigen presentation and diminished type-I interferon signaling, thereby fostering resistance [6].

Importantly, depleting γδ T cells or neutralizing IL-17A restored sensitivity to CDK4/6 inhibitors and increased CD8+ T cell infiltration [6]. Notably, the administration of radiotherapy prior to palbociclib treatment prevents γδ T cell recruitment by inducing a hypoxic, CCL2-deficient tumor microenvironment [6]. Thus, in this context γδ T cells function as mediators of immune evasion rather than effectors of anti-tumor immunity, which stands in contrast to the cytotoxic or regulatory roles traditionally attributed to them [6, 7].

A similar immunosuppressive role for γδ T cells has been described in the study by Rozalén et al. [8]. Investigating tumor-intrinsic hepatitis A virus cellular receptor 2 (HAVCR2, best known as TIM3), the authors show that breast cancer cells expressing high levels of TIM3 remodel early liver metastases by enriching immunosuppressive myeloid populations and reducing the presence of effector lymphocytes, compared to TIM3-knockdown lesions [8]. This immune reprogramming aligns with previous studies implicating IL-17-producing γδ T cells in neutrophil recruitment, suppression of cytotoxic T cell activity, and promotion of metastatic progression [9].

Together, these findings support a model in which IL-17A+ γδ T cells facilitate tumor immune evasion and metastatic outgrowth. In the context of CDK4/6 inhibition, they impair drug efficacy and may contribute to the formation of immune-privileged niches during metastatic seeding (Fig. 1).

<figure><img src="image_4.png" /><figcaption>**Fig. 1** Mechanism of γδ T cell-mediated resistance to CDK4/6 inhibitors in HR⁺HER2⁻ breast cancer. CDK4/6 inhibitor treatment combined with endocrine therapy triggers hypoxia-sensitive cancer cell secretion of the chemokine CCL2. Acting as a chemoattractant, CCL2 recruits IL-17A-producing γδ T cells (CD3⁺CD4⁺CD8⁻IL-17A⁺RORγ⁺) into the tumor microenvironment. These γδ T cells release IL-17A, promoting the repolarization of tumor-associated macrophages (TAMs) toward a CX3CR1⁺ immunosuppressive phenotype. CX3CR1⁺ TAMs display impaired antigen presentation due to downregulated MHC-II expression and weakened type I interferon signaling, fostering an immunosuppressive environment that limits CD8⁺ cytotoxic T lymphocyte (CTL) and activity. This γδ T cell-driven immune evasion ultimately underlies resistance to CDK4/6 inhibition and treatment failure. Notably, radiotherapy administered prior to CDK4/6 inhibition creates a hypoxic tumor microenvironment that directly suppresses CCL2 expression, thereby blocking γδ T cell recruitment.</figcaption></figure>

Edited by Professor Mauro Piacentini

Received: 15 July 2025 Revised: 10 September 2025 Accepted: 13 October 2025
Published online: 14 November 2025
Recognizing γδ T cells as context-dependent drivers of resistance supports the development of therapeutic strategies aimed at neutralizing IL-17A or otherwise modulating γδ T cell activity [10]. Such approaches may enhance the efficacy of both standard endocrine-CDK4/6 targeted regimens and novel immunotherapeutic combinations in HR⁺/HER2⁻ breast cancer.

Oliver Kepp¹,²✉ and Guido Kroemer¹,²,³✉

¹Université Paris Cité, Sorbonne Université, Inserm, Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Institut Universitaire de France, Paris, France. ²Université Paris-Saclay, INSERM US23/CNRS UAR 3655, Metabolomics and Cell Biology Platforms, Institut Gustave Roussy, Villejuif, France. ³Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. ✉email: captain.olsen@gmail.com; kroemer@orange.fr

## DATA AVAILABILITY

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

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7. Ma Y, Aymeric L, Locher C, Mattarollo SR, Delahaye NF, Pereira P, et al. Contribution of IL-17-producing gamma delta T cells to the efficacy of anticancer chemotherapy. J Exp Med. 2011;208:491-503.

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## ACKNOWLEDGEMENTS

The figure was created in BioRender (www.BioRender.com). OK receives funding from Institut National du Cancer (INCa), Association pour la recherche sur le cancer (ARC), the European Innovation Council (EIC) and the Fondation Gustave Roussy. GK is supported by the Ligue contre le Cancer (équipe labellisée); Agence National de la Recherche (ANR-22-CE14-0066 VIVORUSH, ANR-23-CE44-0030 COPPERMAC, ANR-23-R4HC-0006 Ener-LIGHT); ARC; Cancéropôle Ile-de-France; Fondation pour la Recherche Médicale (FRM); European Research Council Advanced Investigator Award (ERC-2021-ADG, Grant No. 101052444; project acronym: ICD-Cancer, project title: Immunogenic cell death (ICD) in the cancer-immune dialog); The ERA4 Health Cardinoff Grant Ener-LIGHT; European Union Horizon 2020 research and innovation programms Oncobiome grant agreement number: 825410, Project Acronym: ONCOBIOME, Project title: Gut OncoMicrobiome Signatures [GOMS] associated with cancer incidence, prognosis and prediction of treatment response, Prevalung (grant agreement number 101095604, Project Acronym:

PREVALUNG EU, project title: Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception), Neutrocure (grant agreement number 861878: Project Acronym: Neutrocure; project title: Development of "smart" amplifiers of reactive oxygen species specific to aberrant polymorphonuclear neutrophils for treatment of inflammatory and autoimmune diseases, cancer and myeloablation); National support managed by the Agence Nationale de la Recherche under the France 2030 program (reference number 21-ESRE-0028, ESR/Equipex+ Onco-Pheno-Screen); Evolution Network on Senescence in Aging (reference HF-E Einstein Network); INCa; Institut Universitaire de France; PAIR-Obésité INCa_1873, the RHUs Immunolife and LUCA-pi (ANR-21-RHUS-0017 and ANR-23-RHUS-0010, both dedicated to France Relance 2030); Seerave Foundation; SIRIC Cancer Research and Personalized Medicine (CARPEM, SIRIC CARPEM INCa-DGOS-Inserm-ITMO Cancer_18006 supported by Institut National du Cancer, Ministère des Solidarités et de la Santé and INSERM). This study contributes to the IdEx Université de Paris Cité ANR-18-IDEX-0001.

## AUTHOR CONTRIBUTIONS

Conceptualization; Writing—original draft: OK has conceptualized the work and has written the original draft. Writing—review & editing; Visualization: OK and GK have reviewed and edited the manuscript and OK has prepared the figure. Supervision OK and GK have jointly supervised the work. All authors have read and approve the final version of the manuscript.

## COMPETING INTERESTS

OK is a scientific co-founder of Samsara Therapeutics. GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Sutro, Tollys, and Vascage. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everimmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Centenara Labs (formerly Rejuveron Life Sciences), Evolution, and Institut Servier. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis, and metabolic disorders. GK's wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9m, Tusk, and Roche, was on the on the Board of Directors of Transgene, is a cofounder of everimmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK's brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The funders had no role in the design of the study; in the writing of the manuscript, or in the decision to publish the results.

## ADDITIONAL INFORMATION

Correspondence and requests for materials should be addressed to Oliver Kepp or Guido Kroemer.

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© The Author(s) 2025