Abnormal cell proliferation is a major hallmark of cancer. Several proteins are involved in the cell cycle, and most of these regulate the positive or negative control of cyclin-dependent kinases. Previous studies have implicated cell-cycle proteins in regulating immune cells and factors of the tumor immune microenvironment (TIME), highlighting their role in regulating tumor immunity.
In a recent review published in the Genes & Diseases journal, researchers at the First Affiliated Hospital of Anhui Medical University summarize the latest on how cell cycle proteins regulate the tumor microenvironment to influence anti-tumor immunity and discuss their associated mechanisms.

The authors provide a brief introduction to cell-cycle proteins, including insights into their classification as positive and negative regulatory proteins, with a focus on the cellular and biochemical composition of the tumor microenvironment (TME).

Positive regulatory cell-cycle proteins, including cyclins (e.g., cyclin J and cyclin G2) and cyclin-dependent kinases (CDK1, CDK2, CDK5, CDK6, CDK7, CDK9, and CDK20), are differentially expressed in various cancers and TME cells, influencing tumor immunity. Their specific inhibition, by CDK inhibitors, may reshape the TME—potentially converting immunologically 'cold' tumors into 'hot' tumors and suppressing tumor progression.

Negative regulatory proteins, like p21 and p16, act mainly by inhibiting CDKs or cyclin-CDK complexes. Knockdown of lincRNA-p21 in TAMs antagonizes p53 expression and promotes M1 macrophage polarization, resulting in tumor inhibition. p21 induces cell cycle arrest and enhances immunosurveillance functions, acting as a biological timer for stressed cells. Similarly, p16INK4a exhibits senescent and tumor-promoting properties by altering the TME.

Inhibition or overexpression of these cycle proteins regulates the TME through different pathways. Previous research has shown that these proteins regulate immune cells, like CTLs, Tregs, macrophages, NK cells, CD4+ T cells, DCs, and MDSCs, which encompass most immune cells of the TME.

Various pan-CDK2 inhibitors (SNS-032), CDK4/6 inhibitors (abemaciclib, palbociclib, and trilaciclib), CDK7 inhibitors (YKL-5-124, THZ1), CDK12/13 inhibitors (SR-4835), and CDK1/2/5 inhibitors (dinaciclib) have been employed in clinical treatment with positive effects. Moreover, the overexpression or inhibition of cell cycle proteins in combination with other inhibitors has been shown to exert a greater effect than either approach alone on tumor regression and prolonged survival in tumor-bearing mice.

In conclusion, this review details the role of cell cycle proteins in regulating antitumor immunity and discusses how CDK inhibitors in combination with other inhibitors exert a therapeutic effect on various tumors.

Reference

Title of the original paper: The roles of cell cycle proteins in regulating the tumor immune microenvironment

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101706

Funding Information:

• Natural Science Foundation of China (No. U21A20375, No. 82300669)
• Natural Science Research Key Project of Anhui Province University (China) (No. 2024AH050816)
• Foundation of Beijing Life Oasis Public Service Center (China) (No. cphcf-2022-021)
• Basic and Clinical Promotion Program of Anhui Medical University (China) (No. 2023xkjT039).

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4 | Impact Factor: 9.4

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