BRIEF RESEARCH REPORT article
Front. Oncol.
Sec. Cancer Immunity and Immunotherapy
The CDK inhibitor Roscovitine enhances the therapeutic efficacy of anti-PD-1 in non-small cell lung cancer
Provisionally accepted
C. Marcela Diaz-Montero
Elise G. Holvey-Bates
Patricia RaymanYvonne ParkerDaniel J. Lindner
George Robert Stark
Sarmishtha De*- Cleveland Clinic, Cleveland, United States
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Abstract Immune checkpoint blockade (ICB) targeting the PD-1/PD-L1 axis has significantly improved outcomes in non-small cell lung cancer (NSCLC), yet many patients fail to respond. High PD-L1 expression, often predictive of response, paradoxically correlates with poor prognosis and immune suppression driven by the tumor microenvironment (TME), including myeloid-derived suppressor cells (MDSCs). Roscovitine (Seliciclib), a cyclin-dependent kinase (CDK) inhibitor, downregulates PD-L1 and exhibits immunomodulatory effects, but its potential to enhance ICB efficacy in NSCLC is unknown. Using a syngeneic, immune-competent Lewis lung carcinoma (LLC) mouse model, we evaluated the therapeutic impact of Roscovitine alone or combined with anti-PD-1 therapy. The combination substantially reduced tumor burden, prolonged survival, and induced durable anti-tumor immunity upon tumor re-challenge. Mechanistically, Roscovitine decreased PD-L1 expression on tumor cells and myeloid populations, including circulating and tumor-infiltrating MDSCs, while reducing CCR2⁺ MDSC frequency in circulation. This was accompanied by increased infiltration of cytotoxic CD8⁺ T cells and NK cells into the tumor, collectively enhancing anti-tumor immune activity within the TME. These findings demonstrate that Roscovitine potentiates anti-PD-1 therapy by simultaneously suppressing immunosuppressive cell populations and amplifying effector immune responses. The dual modulation of PD-L1 expression and immune cell dynamics provides a strong rationale for the clinical evaluation of Roscovitine in combination with immune checkpoint blockade in NSCLC and potentially other solid tumors.
Keywords: Circulating immune cells, combination therapy, Immune Modulation, Non-small cell lung cancer, PD-L1, Tumor-infiltrating immune cells
Received: 13 Nov 2025; Accepted: 08 Dec 2025.
Copyright: © 2025 Diaz-Montero, Holvey-Bates, Rayman, Parker, Lindner, Stark and De. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Sarmishtha De
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