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Tumor Discovery Immunomodulatory effects of CDK4/6 inhibitors

in Figure 3, the inhibition of CDK4/6 diminishes the vessel formation essential for tumor growth and
presence of tumor-infiltrating Tregs, 44,49 thereby reducing metastasis. Although CDK6 has been associated with
immunosuppressive cellular networks and promoting angiogenic regulation, its pharmacological inhibition
an immuno-permissive TME. However, this therapeutic could simultaneously target both tumor proliferation and
approach might also deplete dendritic cells within the vascularization. Given the dual inhibition of CDK4/6,
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TME, potentially hindering immune activation. The these agents might indirectly influence angiogenesis,
adoptive transfer of dendritic cells has been demonstrated even though their mechanisms are less clear compared to
to circumvent this issue, facilitating effective tumor control their immunological effects. A study on CDK4/vascular
when used in conjunction with CDK4/6 inhibitors and endothelial growth factor receptor 2 (VEGFR2) dual-
immune checkpoint blockade. 51 targeting inhibitors showed synergistic suppression of
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Unlike DNA-damaging agents, senescence induced by cancer progression and angiogenesis, yet the direct
CDK4/6 inhibitors is marked by minimal expression of pro- angiogenic effects of standard CDK4/6 inhibitors require
tumorigenic factors, such as IL-6 and CXCL8, resulting in further exploration.
a TME with augmented antitumor properties. Numerous 5.4. Regulation of PD-L1 expression
studies have shown that CDK4/6 inhibition encourages the
infiltration of cytotoxic T-cells into tumors, a critical factor PD-L1, a critical immune checkpoint protein expressed on
for effective antitumor immunity. 27,49,52 In some cases, tumor cell surfaces, suppresses T-cell-mediated immune
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CDK4/6 inhibition also alters tumor-associated macrophage responses through binding to the PD-1 receptor. This
populations, potentially steering their polarization toward interaction facilitates tumor immune evasion by inhibiting
antitumor phenotypes. These coordinated alterations cytotoxic T-cell activity and promoting T-cell exhaustion.
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collectively create an immunologically “hot” TME with To enhance the therapeutic efficacy of combining CDK4/6
diminished immunosuppression, offering a compelling inhibitors with ICIs, comprehending the effect of CDK4/6
basis for combining CDK4/6 inhibitors with cancer inhibitors on PD-L1 expression is crucial, as depicted
immunotherapy. in Figure 4. Studies suggest that CDK4/6 inhibitors can
upregulate PD-L1 expression by activating the nuclear
Beyond their immunomodulatory effects, emerging factor kappa B signaling pathway. Typically, the CDK4/6-
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evidence suggests that CDK4/6 inhibitors may also cyclin D complex facilitates the degradation of PD-L1
impact tumor angiogenesis, the process of new blood through the speckle-type POZ protein-cullin 3 (CUL3)
ubiquitination pathway. However, CDK4/6 inhibition
interferes with this degradation process, leading to the
stabilization of PD-L1 protein levels. This stabilization
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can potentially make tumors more susceptible to

Figure 4. Modulatory effects of CDK4/6 inhibitors on PD-L1 expression.
Figure 3. Mechanisms of CDK4/6 inhibitors in TME reprogramming. CDK4/6 inhibitors upregulate PD-L1 expression and stabilize PD-L1
CDK4/6 inhibitors modulate the TME by acting on a complex ecosystem protein levels, thereby sensitizing tumors to PD-1/PD-L1 blockade
comprising immune cells, vasculature, and stromal components. Image therapies. Image created by the authors.
created by the authors. Abbreviations: CDK4/6: Cyclin-dependent kinase 4 and 6;
Abbreviations: CDK4/6: Cyclin-dependent kinase 4 and 6; NFκB: Nuclear factor kappa B; PD-1: Programmed cell death protein 1;
CXCL8: C-X-C motif chemokine ligand 8; IL6: Interleukin 6; TME: PD-L1: Programmed death ligand-1; Rb: Retinoblastoma; SPOP: Speckle-
Tumor microenvironment. type POZ protein.

Volume 4 Issue 3 (2025) 22 doi: 10.36922/TD025190037