CDK4/6 inhibition enhances CAR-T cell therapy in solid tumors

Mol Ther. 2026 Mar 24:S1525-0016(26)00210-8. doi: 10.1016/j.ymthe.2026.03.024.

Emily J Lelliott ¹, Jonathan Naddaf ², Kun-Hui Lu ³, Katherine D Cummins ², Kelly M Ramsbottom ², David S Reynolds ⁴, Michael Taylor ², Krutika Ambani ⁵, Isabelle Munoz ⁴, Susan Jackson ⁶, Jessica Li ², Cheok Weng Chan ², Kara L Britt ⁷, Paul A Beavis ⁴, Shom Goel ⁸, Jane Oliaro ⁹

Affiliations

1 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: [email protected].
2 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
3 Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
4 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
5 Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
6 Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.
7 Cancer Evolution and Metastasis Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia.
8 Cancer Biology and Therapeutics Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: [email protected].
9 Cancer Immunology Program, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: [email protected].

PMID: 41883164 DOI: 10.1016/j.ymthe.2026.03.024

Abstract

CDK4/6 inhibitors promote anti-tumor immunity through diverse mechanisms, positioning them as promising adjuvants to Cancer immunotherapies. While CDK4/6 inhibitors have demonstrated strong synergy with immune checkpoint inhibitors across numerous preclinical Cancer models, their combination with CAR-T cell therapy remains unexplored. In this study, we examined the efficacy of combined CDK4/6 inhibition (trilaciclib) and CAR-T therapy across a range of preclinical blood and solid Cancer models. In vitro, trilaciclib enhanced human CAR-T cell cytotoxicity and metabolic fitness while reducing expansion. In vivo, the combination outperformed single agents against retinoblastoma protein (RB)-proficient, trilaciclib-sensitive CD19+ leukemia. However, in an equivalent RB-deficient model, the combination therapy was no more effective than CAR-T cells alone, suggesting that enhanced CAR-T cell function may be offset by reduced expansion. In contrast, in solid Cancer models the combination was consistently more efficacious than either monotherapy. Notably, combination effects were most pronounced in immunocompetent mouse models, including a model with poor sensitivity to trilaciclib as a monotherapy. Mechanistically, CDK4/6 inhibition reduced tumor-infiltrating T-regulatory cells while enhancing CD8+ CAR-T cell persistence, tumor trafficking, and cytotoxic function within the tumor. Together, these findings suggest that trilaciclib and CAR-T cell therapy may be an effective combinatorial treatment for solid cancers.

Keywords

CAR-T cell therapy; CDK4/6 inhibitor; RB-proficient tumors; T cell metabolism; cancer immunotherapy; combination therapy; hematologic malignancies; preclinical cancer models; solid tumors; trilaciclib.

Products

Cat. No.

Product Name

Description

Target

Research Area
HY-50767

Palbociclib

99.94%, CDK4/6 Inhibitor

CDK

Cancer

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