Enhancer of zeste homolog 2 inhibitors (EZH2i) have garnered increased attention owing to their anticancer activity by targeting EZH2, a well-known cancer-promoting factor. However, some lymphomas are resistant to EZH2i, and EZH2i treatment alone is ineffective in case of EZH2-overexpressing solid tumors. The anti-cancer efficacy of EZH2i may be improved through safe and effective combinations of these drugs with other treatment modalities. Preclinical evidence indicates that combining EZH2i with other therapies, such as immunotherapy, chemotherapy, targeted therapy, and endocrine therapy, has complementary or synergistic antitumor effects. Therefore, elucidating the underlying mechanisms of the individual constituents of the combination therapies is fundamental for their clinical application. In this review, we have summarized notable clinical trials and preclinical studies using EZH2i, their progress, and combinations of EZH2i with different therapeutic modalities, aiming to provide new insights for tumor treatment.

Sensitivity has been a key issue for Enhancer of zeste homolog 2 (EZH2) inhibitors in cancer therapy. The EZH2 inhibitor EPZ-6438 was first approved by the US Food and Drug Administration (FDA) in 2020. However, its inadequate anti-cancer activity in solid tumors limits its clinical application. In this study, we utilized the multiple cancer cell lines, which are less sensitive to the EZH2 inhibitor GSK126, combining animal model and clinical data to investigate the underlying mechanism. IncuCyte S3 was used to explore the difference in the responsiveness of hematological tumor cells and solid tumor cells to GSK126. Transcriptome and metabolome of B16F10 cells after GSK126 treatment were analyzed and the distinct changes in the metabolic profile were revealed. Real-time quantitative PCR and western blot experiments were used to further verify the multi-omics data. ChIP-qPCR was performed to detected H3K27me3 enrichment of target genes. Finally, the anti-tumor effects of combining GSK126 and lipid metabolism drugs were observed with IncuCyte S3 platform, CCK-8 and animal model respectively. We found that although the proliferative phenotype did not show strong difference upon treatment with GSK126, the transcriptome and metabolome changed profoundly. GSK126 treatment led to broad shifts in glucose, amino acid, and lipid metabolism. Lipid synthesis was strengthened manifested by the increasing abundance of unsaturated fatty acids. SCD1 and ELOVL2 were regulated by H3K27me3 at gene regulatory region, and upregulated by EZH2 knockdown and inhibitors. SCD1 knockdown increased cellular sensitivity to GSK126. Based on the findings above, the application of the combination with SCD1 inhibitor significantly attenuated the proliferation of cancer and increased the sensitivity to GSK126 by suppressing desaturation of fatty acids. Dysregulated lipid metabolism can blunt the sensitivity of cancer cells to GSK126. These characteristics shed light on the novel combination therapy strategies to combat tumor resistance. National Natural Science Foundation of China (No. 81672091, No.91749107 and No. 81972966).

Placenta Accreta Spectrum (PAS) is a severe obstetric disorder characterized by excessive trophoblast invasion into the uterine myometrium, leading to life-threatening hemorrhage at delivery. While closely monitored, the molecular drivers of its progression remain poorly defined, hindering predictive and therapeutic strategies. Here, we employed longitudinal quantitative proteomics on maternal plasma from five PAS patients across gestation. We identified Keratin 6A (KRT6A) as a key biomarker whose plasma levels increase with PAS progression. Immunohistochemistry confirmed the specific upregulation of KRT6A in trophoblasts at the maternal–fetal interface in PAS. Functional studies demonstrated that KRT6A overexpression significantly enhances the migration and invasion capabilities of trophoblast cell lines in vitro, without affecting proliferation or apoptosis. Integrative bioinformatics analysis linked KRT6A to the activation of the MYC signaling pathway, a known driver of invasiveness. Our data establish KRT6A as a plasma biomarker correlating with PAS severity and a functional regulator of trophoblast invasiveness. These findings suggest a novel mechanism wherein KRT6A-mediated enhancement of trophoblast invasion, potentially via MYC signaling, contributes to PAS pathogenesis. This work provides a potential circulating biomarker for monitoring PAS progression and implicates KRT6A as a candidate therapeutic target for mitigating excessive placental invasion.