Abstract Background: Tumor-derived signals can reprogram immune cells and platelets to support cancer progression. However, the regulatory mechanisms underlying this systemic education are not well understood. Methods: RNA sequencing was performed on isolated platelet and white blood cell fractions from breast cancer patients and on THP-1 monocytes exposed to triple-negative breast cancer (TNBC) MDA-MB-231 cells. Transcriptomic data was analyzed using Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA) to identify upstream regulators and enriched pathways. Results: In both clinical and in-vitro datasets, CDK6 emerged as a key upstream regulator. In patient-derived platelets, CDK6 was identified as a major activated regulator in cancer versus non-cancer samples suggesting a role in tumor-driven systemic remodeling. The CDK6 regulatory network included upregulated and downregulated genes that were significantly modulated. In THP-1 monocytes following contact with TNBC cells, CDK6 activation was confirmed by IPA and accompanied by GSEA enrichment of cell cycle-related pathways such as “regulation of cell cycle process.” Functionally, THP-1 cells exposed to TNBC cells or conditioned media displayed increased proliferation, indicating tumor-induced monocyte reprogramming. This effect was reversed by CDK4/6 inhibitors, highlighting a new immunomodulatory mechanism of these standard-of-care drugs. Conclusions and Translational Relevance: CDK4/6 activation represents a shared hallmark of tumor education across immune and platelet compartments. These findings reveal a novel mechanism of systemic immune modulation and suggest that CDK4/6 inhibitors can reverse oncogenic activation in monocytes and platelets. This study extends the relevance of these agents beyond tumor cell-intrinsic effects. Targeting CDK6-dependent immune reprogramming may offer a novel strategy to disrupt systemic tumor-immune crosstalk and improve therapeutic responses in breast cancer. Citation Format: Karen Norek, Jacob Kennard, Kenneth Fu, Robert Shepherd, Kristina Rinker, Olesya Kharenko. New role for CDK6 activation in tumor-induced monocyte and platelet reprogramming in breast cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3520.
Norek et al. (Fri,) studied this question.