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Tumor Discovery Immunomodulatory effects of CDK4/6 inhibitors

molecular vulnerabilities within cancer cells. A pivotal Given these intriguing and evolving mechanisms, a
breakthrough in this evolution has been the development thorough investigation into combining CDK4/6 inhibitors
of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, with ICIs is warranted to elucidate their biological
which have revolutionized the treatment of hormone interactions and therapeutic potential. This review
receptor-positive (HR ), human epidermal growth factor examines the promise of such combination strategies,
+
receptor 2-negative (HER2 ) metastatic breast cancer examining the scientific rationale, present clinical evidence,
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(MBC). These agents exert their therapeutic effects by and challenges associated with this approach.
1
inducing cell cycle arrest, thereby inhibiting tumor cell
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proliferation. CDK4/6 inhibitors, including palbociclib, 2. The effects of CDK4/6 inhibitors
ribociclib, and abemaciclib, have demonstrated impressive 2.1. Primary mechanisms of CDK4/6 inhibitors
efficacy in combination with endocrine therapy, +
significantly prolonging progression-free survival (PFS) In HR breast cancer, estrogen signaling upregulates
and, in some cases, overall survival (OS). Emerging cyclin D expression, activating CDK4/6 to drive cell cycle
1,3
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evidence, however, suggests that the biological impact of progression. The subsequent molecular cascade is highly
these inhibitors extends beyond their canonical role in coordinated across distinct cell cycle phases: G1 (growth),
cell cycle regulation, revealing complex and multifaceted S (DNA synthesis), G2 (pre-mitotic expansion), and
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effects on tumor biology. Notably, these inhibitors exhibit M (mitosis). CDKs are key orchestrators, with cyclin
immunomodulatory properties that are capable of D-CDK4/6 complexes serving as master regulators of the
1
reprogramming the tumor microenvironment (TME). G1/S checkpoint. These complexes initiate retinoblastoma
(Rb) protein phosphorylation, inactivating this tumor
Immune checkpoint inhibitors (ICIs) have also suppressor and liberating E2F transcription factors to
revolutionized cancer therapy by targeting regulatory activate genes required for S-phase progression. The
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proteins on immune cells, such as T cells, which normally estrogen-CDK4/6 signaling axis, therefore, represents a
act as natural “brakes” to limit immune responses. By unique therapeutic vulnerability in HR breast cancers,
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releasing these immune “brakes,” ICIs enhance the body’s explaining their exceptional sensitivity to CDK4/6 inhibitors,
ability to recognize and eliminate cancer cells. Key particularly when combined with endocrine therapy.
4
immune checkpoint proteins targeted by ICIs include Building upon this molecular framework, CDK4/6
programmed cell death protein 1 (PD-1) and its ligand, inhibitors exert their therapeutic effects by blocking
programmed death-ligand 1 (PD-L1), as well as cytotoxic Rb phosphorylation, thereby maintaining its growth-
T-lymphocyte-associated protein 4 (CTLA-4). While ICIs suppressive hypophosphorylated state. This inhibition
5
have demonstrated remarkable success in treating various prevents E2F-mediated transcriptional activation of S-phase
cancer, including melanoma, lung cancer, and Hodgkin genes, resulting in potent G1 cell cycle arrest. 12,13 While
lymphoma, their efficacy as monotherapy in HR /HER2 sharing this core mechanism, CDK4/6 inhibitors display
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breast cancer remains limited. This reduced activity may distinct pharmacological characteristics. For instance,
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stem from the relatively low tumor-infiltrating lymphocyte abemaciclib demonstrates greater selectivity for CDK4
(TIL) density and low tumor mutational burden over CDK6 and exhibits enhanced blood–brain barrier
characteristic of this breast cancer subtype, suggesting penetration, potentially offering advantages in specific
a less immunogenic TME. The modest success of ICIs as clinical scenarios. It also exhibits off-target effects by
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single agents in HR /HER2 breast cancer underscores the inhibiting additional cyclin-dependent kinases, such as
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need to explore combination strategies that may enhance CDK2/Cyclin A/E and CDK1/Cyclin B complexes. These
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tumor immunogenicity and improve immune response differential properties translate to varied biological outcomes,
efficacy. including G2 phase arrest, cell death in Rb phosphorylation-
Emerging evidence supports the therapeutic rationale deficient cells, and characteristic transcriptional signatures
for combining CDK4/6 inhibitors with immunotherapy in observed across experimental systems.
HR /HER2 breast cancer. These inhibitors exhibit distinct
+
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immunomodulatory properties, including enhanced tumor 2.2. Modulating other cellular processes
antigen presentation and reduced immunosuppressive Beyond their well-characterized roles in cell cycle control,
regulatory T cells (Tregs), which may potentiate the efficacy CDK4/6 inhibitors exert profound impacts on diverse
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of immune-based therapies. The intersection of cell cycle cellular processes through intricate molecular interactions.
regulation and immune response represents an exciting Depending on specific cellular microenvironments, these
and evolving area of oncological research, challenging inhibitors can induce either cellular quiescence or trigger
traditional paradigms of cancer treatment. 8 senescence. This dual regulatory capability provides a

Volume 4 Issue 3 (2025) 17 doi: 10.36922/TD025190037