Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype characterized by an immunosuppressive tumor microenvironment and resistance to chemotherapy. Previous studies have indicated that apolipoprotein C-II (APOC2) is involved in the immune microenvironment of several malignancies and is upregulated in breast cancer; however, the molecular mechanisms through which APOC2 regulates the immune microenvironment in TNBC remain poorly understood. In the present study, we found that APOC2 was upregulated in TNBC tissues and was negatively correlated with M1 macrophage infiltration. APOC2 overexpression in 4 T1 cells promoted tumor progression by enhancing cell proliferation, migration, and invasion, while suppressing M1 macrophage polarization. In addition, KLHL1, a substrate adaptor for the Cullin3-RING E3 ubiquitin ligase complex, was found to interact with APOC2, and KLHL1 overexpression reversed the biological effects induced by APOC2. Mechanistically, KLHL1 promoted APOC2 protein degradation through the ubiquitin-proteasome pathway, thereby enhancing M1 macrophage polarization and suppressing the malignant behavior of tumor cells. Finally, in vivo xenograft experiments demonstrated that APOC2 reduced M1 macrophage polarization and increased tumor weight and volume, whereas KLHL1 overexpression counteracted the oncogenic effects of APOC2. Collectively, these findings reveal that activation of the KLHL1/APOC2 axis enhances M1 macrophage polarization and inhibits TNBC progression, providing novel insights into the immune regulatory mechanisms underlying TNBC development.
Ziran He, Zhenhua Zhang, Li Ding et al.· Biochimica et Biophysica Act...· 0 citations
INTRODUCTION
CDK4/6 kinases are crucial cell cycle regulators, and pharmacological inhibition of these kinases to block the G1-to-S phase transition has become an integral part of modern cancer therapy. Although five CDK4/6 inhibitors have been clinically approved, the development of acquired drug resistance greatly limits their long-term therapeutic efficacy.
METHODS
This review systematically summarizes the latest advances in CDK4/6 inhibitor research from 2022 to 2025, focusing on their structural features, biological functions, and preclinical research progress. In addition, this article comprehensively explores emerging therapeutic strategies, including bifunctional molecules and PROTAC-based protein degraders.
RESULTS
The action mechanisms of conventional CDK4/6 inhibitors have been relatively well elucidated. Notably, these emerging strategies have yielded encouraging preclinical results, including co-targeting CDK4/6 with other critical therapeutic nodes (e.g., HDAC, PARP1) and adopting PROTAC-based degraders to directly induce the degradation of target proteins. A growing number of innovative approaches targeting drug resistance via multi-target inhibition and induced protein degradation have been developed. Distinct from classical singletarget monotherapy, these innovative strategies leverage distinct pharmacological pathways, offering feasible research directions to improve therapeutic efficacy and delay drug resistance.
DISCUSSION
In-depth understanding of CDK4/6 inhibitors and the continuous development of bifunctional agents and protein degraders provides key theoretical and technical support for the design of next-generation therapeutic strategies to address current clinical limitations. These research advances are expected to facilitate the development of more effective and long-lasting therapeutic modalities for tumor treatment.
CONCLUSION
This review summarizes recent advances in CDK4/6 inhibitors. Novel dual-target and PROTACbased strategies offer promising resistance-overcoming tumor therapies.
Miao-Xia Pu, Wenbo Xu, Li Ding et al.· Anti-Cancer Agents in Medici...· 0 citations
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