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Tumor Discovery Immunomodulatory effects of CDK4/6 inhibitors

the exact mechanisms are not fully elucidated, available
data suggest that these inhibitors can enhance NK
cell activation and increase their cytotoxic capabilities
(Figure 1). For instance, CDK4/6 inhibitors have been
shown to elevate the expression of intercellular adhesion
molecule 1, which facilitates the recognition of tumor
cells by NK cells. There is a growing consensus that the
36
combination of CDK4/6 inhibitors with other agents, such
as MEK inhibitors, may enhance NK cell-mediated tumor
elimination through senescence-associated secretory
37
phenotype (SASP) factors. In addition, these inhibitors
might influence the formation of the immune synapse
between NK cells and tumor cells, potentially amplifying
NK cell-mediated cytotoxicity against tumor cells. 38,39

5.1.3. Modulation of macrophage polarization Figure 2. The specific roles of CDK4/6 inhibitors in augmenting tumor
cell immunogenicity. Image created by the authors.
CDK4/6 inhibitors have been shown to influence Abbreviations: CDK4/6: Cyclin-dependent kinase 4 and 6; cGAS-STING:
macrophage polarization within the TME. Recent findings Cyclic GMP-AMP synthase-stimulator of interferon genes; DNMT:
suggest that these inhibitors can induce a transition in DNA methyltransferase; ERV: Endogenous retroviruses; IFN: Interferon;
macrophage phenotype from the immunosuppressive MHC: Major histocompatibility complex; Rb: Retinoblastoma.
macrophage M2 state to the tumoricidal macrophage
M1 phenotype (Figure 1). Specifically, treatment with enhances the presentation of MHC-I molecules, making
40
46
abemaciclib has been associated with elevated levels of tumors more immunogenic. In addition, these inhibitors
CSF-2, a cytokine that is pivotal for fostering macrophage activate the cyclic GMP-AMP synthase-STING pathway,
M1 polarization and enhancing major histocompatibility driving IFN-I production and amplifying innate immune
responses. Finally, CDK4/6 inhibitors prime antigen-
47
complex (MHC) II expression in dendritic cells. In
41
addition, ribociclib has been observed to decrease the presenting cells, such as dendritic cells and macrophages,
expression of immunosuppressive chemokines, including promoting the activation of Th1/Th2 pathways and playing
48
C-C motif chemokine ligand (CCL)2, CCL7, and CCL22, crucial roles in adaptive immunity.
which play a role in the chemotaxis and differentiation CDK4/6 inhibitors enhance tumor immunogenicity by
of immunosuppressive cells, such as macrophage M2. upregulating the surface expression of MHC-I molecules,
41
+
This modulation of macrophage polarization is believed which are essential for antigen presentation to CD8 T
to enhance antitumor immune responses. However, the cells that recognize and eliminate tumor cells. 44,49 Research
specific molecular pathways through which CDK4/6 has shown that palbociclib treatment increases MHC-I
inhibitors reprogram macrophages are not yet fully expression in melanoma cell lines and alters the MHC-I
understood. 42 peptide repertoire, thereby enhancing immunogenicity.
50
This effect is mediated through the transcriptional
5.2. Enhancing tumor cell immunogenicity activation of the antigen processing and presentation
CDK4/6 inhibitors enhance the visibility of tumor cells machinery, including genes encoding proteasomes,
to the immune system by modulating immunogenic transporter-associated antigen processing complexes, and
signaling pathways (Figure 2). They activate the IFN MHC-I subunits. Notably, CDK4/6 inhibitors also increase
response, promote the secretion of IFN-γ, and enhance MHC-II expression in tumor cells. 44,49 Mechanistically,
the activity of IFN-stimulated genes, thereby improving they restore IFN-γ-induced MHC-II transcription by
43
the immune system’s ability to recognize cancer cells. inhibiting the phosphorylation of the Rb protein. 36,41 In
CDK4/6 inhibition induces the production of IFN-I in breast cancer and lymphoma models, abemaciclib and
tumor cells, which in turn stimulates the secretion of T-cell palbociclib have been shown to increase MHC-II levels,
chemokines, facilitating the recruitment of T-cells to the thereby augmenting T-cell activation. 41
tumor site and strengthening antitumor immunity. 44,45
Furthermore, CDK4/6 inhibitors trigger epigenetic 5.3. Remodeling the TME
remodeling by suppressing DNA methyltransferases, CDK4/6 inhibitors have emerged as pivotal modulators
leading to the upregulation of endogenous retroviruses. of the TME, a complex ecosystem comprising immune
This cascade increases the production of IFN-III and cells, vasculature, and stromal components. As illustrated

Volume 4 Issue 3 (2025) 21 doi: 10.36922/TD025190037