image: (A) CDK1 is highly expressed in lung adenocarcinoma tumor tissue, and CDK1 expression is positively correlated with CXCL8 expression in macrophages, forming an immunosuppressive microenvironment through macrophages and thereby promoting tumor progression. Inhibition of CDK1 down-regulates the transcriptional activation of CXCL8 and reverses the macrophage-induced immunosuppressive microenvironment, thereby inhibiting tumor proliferation. (B) The level of the cyclin E/CDK2 complex is increased in basal-like/TNBC cells, and SNS-032 has a potent inhibitory effect on CDK2. SNS-032 treatment can generate a large amount of cell debris by killing tumor cells, thus promoting T lymphocyte recruitment and activating the immune system’s antitumor surveillance arm. Further studies showed that SNS-032 could up-regulate the expression of PD-L1 in some surviving TNBC cells. The combination of SNS-032 with avelumab can enhance the cytotoxicity of NK cells, thereby triggering NK cell-mediated antibody-dependent cell-mediated cytotoxicity. (C) On the one hand, IFN-γ stimulation of medulloblastoma cells can stimulate IRF-1-driven PD-L1 transcription. On the other hand, IFN-γ stimulates p35 expression, thereby increasing CDK5 activity. CDK5 can reduce the abundance of the IRF2/IRF2BP2 inhibitor complex through the action of an unknown kinase, thereby relieving the inhibition of PD-L1 transcription. Specific knockout of the CDK5 gene down-regulated the expression of PD-L1 in tumor cells, increased the number of CD8+ T cells in the microenvironment, and decreased the number of Tregs.
Credit: Qingbo Zhu, Xiaoli Wei, Ziting Qu, Lili Lu, Yiyin Zhang, Hua Wang
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
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