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Tumor Discovery Immunomodulatory effects of CDK4/6 inhibitors

refined strategy for managing cellular behavior. For both in vitro and in vivo (Table 1). In vitro research
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instance, the induction of quiescence in normal tissue has demonstrated that CDK4/6 inhibition can
cells preserves cellular function and prevents aberrant significantly enhance antitumor immunity through
proliferation, while the promotion of senescence in cancer various mechanisms. For instance, it promotes T-cell
cells effectively suppresses their growth and division. activation and triggers antitumor responses by inducing

CDK4/6 inhibitors regulate autophagy in a manner the expression of endogenous retroviral elements in
dependent on cell type and pathophysiological context, tumor cells, thereby increasing antigen presentation
thereby introducing cellular response intricacies and and inhibiting the proliferation of Tregs. 8,20 In addition,
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profoundly impacting survival and functionality. Notably, CDK4/6 inhibition has been shown to inhibit p73
their suppression of autophagy in specific cancer models phosphorylation and activate death receptor 5 (DR5),
may enhance the efficacy of chemotherapy or radiotherapy. potentially enhancing the efficacy of chemotherapy and
immune checkpoint blockade, while also promoting
A particularly notable impact of these inhibitors is immunogenic cell death in cancer cells. Notably,
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their capacity to reprogram tumor cell metabolism by the CDK4/6 inhibitor abemaciclib, when combined
disrupting the balance between anabolism and catabolism. with low-dose radiotherapy, creates an inflammatory
This alteration modifies the synthesis and utilization of TME in Rb-deficient small cell lung cancer, thereby
key metabolites, potentially impairing energy supply enhancing antitumor immune responses to PD-1
mechanisms and survival strategies in cancer cells. blockade. Other findings have highlighted alterations
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Consequently, malignant cells may become more in TBK1 phosphorylation that inhibit the stimulator of
responsive to other anticancer therapies. interferon (IFN) genes (STING) signaling pathway in
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2. Mechanism of ICIs prostate cancer, the use of mesoporous polydopamine
for targeted delivery of CDK4/6 inhibitors to improve
The immune system maintains self-tolerance and prevents synergistic immunotherapy in breast cancer, and the
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excessive immune responses through a sophisticated promotion of chemokine-mediated T-cell recruitment
regulatory network known as immune checkpoints. These to breast tumors through metabolic regulation.
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checkpoints involve interactions between specific proteins Furthermore, single-cell profiling has been highlighted as
expressed on immune cells, such as T cells, and their a tool to guide combination immunotherapy for CDK4/6
corresponding ligands on other cells, including tumor cells. inhibitor-resistant HER2 breast cancer, overcoming
+
PD-1 is an inhibitory receptor expressed on activated T-cells, resistance and enhancing treatment efficacy. 26
while its ligand, PD-L1, is frequently overexpressed on
tumor cells and antigen-presenting cells. Upon PD-1/PD-L1 Furthermore, CDK4/6 inhibitors have been found
binding, inhibitory signals are transmitted to T-cells, leading to induce T-cell-inflamed TME, enhancing the efficacy
to T-cell exhaustion and diminished antitumor activity. of PD-L1 checkpoint blockade and leading to delayed
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CTLA-4 is another critical inhibitory receptor on T cells. tumor growth and complete regression when combined
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CTLA-4 primarily functions during early T-cell activation with anti-PD-L1. These inhibitors also boost the efficacy
by outcompeting the costimulatory receptor CD28 for of oncolytic viruses by increasing tumor-selective cell
binding to B7 proteins on antigen-presenting cells, thereby killing and T-cell activation in refractory glioblastoma,
suppressing T-cell responses. ICIs, typically monoclonal significantly inhibiting tumor growth and prolonging
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antibodies, are designed to disrupt these protein-ligand survival. Pharmacological inhibition of CDK4/6 and
interactions. For example, anti-PD-1 antibodies, such as mitogen-activated protein kinase/extracellular signal-
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nivolumab and pembrolizumab, block PD-1 on T-cells, regulated kinase kinase (MEK) has been shown to induce
preventing PD-L1 engagement and restoring T-cell cytotoxic robust cell cycle arrest and interferon (IFN)-related genes,
activity. Anti-PD-L1 antibodies, such as atezolizumab and leading to separable cell cycle arrest and immune responses
durvalumab, achieve similar effects by directly targeting in RAS-mutant disease models. Innovative approaches,
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PD-L1 on tumor cells. Anti-CTLA-4 antibodies, such as such as the use of self-assembled natural triterpenoid
ipilimumab, enhance early T-cell activation by inhibiting compounds for delivering CDK4/6 inhibitors, have also
CTLA-4-mediated suppression. 19 been explored to improve cancer chemotherapeutic
immunotherapy. 30
3. Research on the immunomodulatory In vivo studies in animal models have further
effects of CDK4/6 inhibitors corroborated the antitumor potential of CDK4/6 inhibition.

Recent studies have illuminated the multifaceted These studies have shown that CDK4/6 inhibition promotes
immunomodulatory effects of CDK4/6 inhibitors antitumor immunity by inducing T-cell memory, thereby

Volume 4 Issue 3 (2025) 18 doi: 10.36922/TD025190037