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Tumor Discovery Immunomodulatory effects of CDK4/6 inhibitors

develops after 1–2 years of treatment, posing a significant activator of transcription 1, interferon regulatory factor 9,
challenge for long-term disease management. ICIs have and SP100, along with suppression of immunostimulatory
emerged as a potential strategy to overcome or delay genes, such as inducible T-cell costimulatory (ICOS) and
resistance to CDK4/6 inhibitors. Pre-clinical evidence CD70, are strongly associated with treatment resistance.
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suggests that CDK4/6 inhibition can modulate immune The precise mechanisms driving resistance to CDK4/6
responses, potentially enhancing the efficacy of ICIs. This inhibitor-immunotherapy combinations remain poorly
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combination approach offers two potential mechanisms: characterized, hindering the clinical optimization of these
Either delaying resistance development when used treatments.
concomitantly or restoring treatment sensitivity when
ICIs are introduced after CDK4/6 inhibitor failure. Early 7.4. Future prospective
clinical trials evaluating palbociclib combined with CDK4/6 inhibitors have shown significant potential in
pembrolizumab and endocrine therapy have shown breast cancer immunotherapy, with ongoing research
encouraging response rates and PFS benefits, particularly targeting several key areas. In early-stage breast cancer,
in treatment-naïve patients and those with stable disease abemaciclib has demonstrated the capacity to reduce the
on prior CDK4/6 inhibition. Introducing ICIs after risk of recurrence. In addition, numerous studies are
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85
CDK4/6 inhibitor failure may be an effective strategy to investigating the synergistic effects of combining CDK4/6
restore treatment sensitivity. By reactivating the immune inhibitors with ICIs to enhance immune responses and
response against tumor cells, ICIs can overcome resistance improve clinical outcomes. Importantly, the therapeutic
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mechanisms, transforming immunologically “cold” tumors applications of these agents have expanded to include
into “hot” ones. In addition, studies have shown that HER2 and triple-negative breast cancer subtypes, where
+
CDK4/6 inhibitors can enhance the immunogenicity of they have shown clinical benefits. 87
tumor cells by modulating the expression of genes related to While research on CDK4/6 inhibitors has predominantly
antigen presentation, thereby improving the effectiveness focused on breast cancer, there is growing interest in their
of immunotherapy. This combined treatment strategy application to other cancer types. In ovarian cancer, both
offers new possibilities for addressing resistance issues in preclinical and clinical studies are exploring the potential
tumor immunotherapy. 42,81 While these preliminary results of CDK4/6 inhibitors as monotherapy or in combination
suggest ICIs may help address resistance mechanisms, treatments. Preliminary evidence indicates that, while
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further investigation is required to validate these findings BRAF and MEK inhibitors have inherent antitumor
and elucidate the underlying biological interactions. effects, their combination with CDK4/6 inhibitors could
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7.3. Challenges and potential limitations further enhance immune activation. Many clinical
trials are currently assessing the safety and efficacy of
Despite their proven efficacy, the clinical use of CDK4/6 these combined strategies, aiming to identify predictive
inhibitors, particularly in HR breast cancer, encounters biomarkers for treatment response and resistance. This
+
several challenges. First, clinical observations have would optimize therapeutic outcomes across various
highlighted potential adverse effects, including hepatitis cancers through synergistic CDK4/6 inhibition. 41
and pneumonitis, which may be linked to increased
secretion of pro-inflammatory cytokines and impaired Treg Recent studies have drawn attention to the potential of
function. Second, combination therapies often require metal ions, such as selenium, zinc, and copper, as critical
41
dose reductions due to overlapping toxicities, resulting in immunomodulatory trace elements that may enhance the
suboptimal drug exposure and potentially compromised efficacy of CDK4/6 inhibitors. 90,91 This enhancement is
efficacy. A significant issue with these combination achieved by reprogramming immunometabolic pathways
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regimens is the increased toxicity, particularly immune- within the TME. Specifically, selenium bolsters T-cell
related adverse events and hematological toxicities, which resilience against oxidative stress through nuclear factor
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92
must be carefully monitored and managed. Determining erythroid 2-related factor 2-mediated antioxidant responses.
the optimal sequence and dosage of these drugs is Meanwhile, zinc aids T-cell proliferation through zeta-chain
essential. Third, approximately 30% of breast cancer of T-cell receptor-associated protein kinase 70 signaling and
93,94
patients exhibit intrinsic resistance to CDK4/6 inhibitors. modulates PD-L1 expression on dendritic cells. These
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Notably, while these drugs enhance antitumor immunity, mechanisms indicate promising opportunities for synergistic
resistance mechanisms frequently involve dysregulated combination therapies that target both cell cycle regulation
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IFN signaling and SASP. For instance, De Angelis et al. and immunometabolic checkpoints.
demonstrated that high IFN-response gene signatures, It is crucial to note that present evidence largely stems
characterized by upregulation of signal transducer and from early-phase clinical trials and pre-clinical models.

Volume 4 Issue 3 (2025) 25 doi: 10.36922/TD025190037