Background: Tumor-associated macrophages (TAMs) are prevalent in advanced ovarian cancer tissues and ascites, significantly influencing disease prognosis. However, the mechanisms driving TAM polarization and their tumor-promoting effects remain poorly understood. Methods: The subcellular distribution of SNX10 in ovarian cancer tissues was analyzed using single-cell datasets (GSE147082, GSE58937). The Kaplan–Meier Plotter and GEPIA2 databases were used to evaluate SNX10’s prognostic relevance. Lentivirus-mediated SNX10 overexpression in THP-1 cells was employed in tumor cell–macrophage co-culture experiments. Transwell assays and flow cytometry assessed SNX10’s effects on ovarian cancer cell metastasis and cisplatin-induced apoptosis. RNA sequencing, Western blotting, lysosomal pH detection, lipid droplet staining, and RT-qPCR were performed to explore SNX10’s molecular mechanisms in TAM polarization and immune modulation. Results: SNX10 was specifically expressed in TAMs, promoting their polarization into the M2 phenotype. This enhanced the migration and invasion of ovarian cancer cell lines A2780 and A2780/CP70 while reducing cisplatin-induced apoptosis. SNX10 decreased lipid droplet content, downregulated p-mTOR1, and impaired lysosomal function in TAMs. Additionally, SNX10 differentially modulated PD-L1 mRNA expression in platinum-sensitive and platinum-resistant ovarian cancer cells. Conclusions: SNX10 regulates the mTOR1/lysosome pathway in TAMs, influencing lipid metabolism and indirectly modulating ovarian cancer cell metastasis. It also alters PD-L1 mRNA expression, suggesting a role in shaping the tumor immune microenvironment.

Background: Small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare and aggressive cancer with a poor prognosis and limited treatment options. Current chemotherapy regimens are predominantly platinum-based; however, the development of platinum resistance during treatment significantly worsens patient outcomes. Everolimus, an mTOR inhibitor, has been widely used in combination cancer therapies and has successfully enhanced the efficacy of platinum-based treatments. Method: In this study, we investigated the combined effects of everolimus and cisplatin on SCCOHT through both in vitro and in vivo experiments, complemented by RNA sequencing (RNA-seq) analyses to further elucidate the therapeutic impact. Result: Our findings revealed that everolimus significantly inhibits the proliferation of SCCOHT cells, induces cell cycle arrest, and accelerates apoptosis. When combined with cisplatin, everolimus notably enhances the therapeutic efficacy without increasing the toxicity typically associated with platinum-based drugs. RNA-seq analysis uncovered alterations in the expression of apoptosis-related genes, suggesting that the underlying mechanism involves autophagy regulation. Conclusions: Despite the current challenges in treating SCCOHT and the suboptimal efficacy of platinum-based therapies, the addition of everolimus significantly suppresses tumor growth. This indicates that everolimus enhances cisplatin efficacy by disrupting survival-promoting signaling cascades and inducing cell cycle arrest. Furthermore, it points to potential biomarkers for predicting therapeutic response.

Objectives: The anticancer effects of PI3Kα inhibitors (PI3Ki) are constrained by their hyperglycemic side effects, while the efficacy of conventional hypoglycemic agents, such as insulin, metformin, and SGLT-2 inhibitors, in mitigating PI3Ki-induced hyperglycemia remains suboptimal. Dorzagliatin, a novel glucokinase activator, has been approved in China for the management of hyperglycemia, offering a promising alternative. This study aims to investigate the pharmacokinetic properties and potential mechanisms of drug interactions of dorzagliatin in the regulation of PI3K-induced hyperglycemia. Methods: Plasma concentrations of WX390, BYL719, and Dorz in mice were measured using high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Pharmacokinetic (PK) parameters and PK/PD models were derived by using Phoenix WinNonlin 8.3.5 software. Blood glucose levels at various time points and tumor volume changes over a four-week period were assessed to explore the interactions when PI3Ki were combined with dorzagliatin. Results: The results indicated that, compared to the Dorz group, the combination groups (Dorz + BYL719, Dorz + WX390) exhibited increases in ${\mathrm{A}\mathrm{U}\mathrm{C}}_{0\to t}$ of dorzagliatin by 41.65% and 20.25%, and in C_max by 33.48% and 13.32%, respectively. In contrast, co-administration of these PI3Ki with dorzagliatin resulted in minimal increase in their plasma exposure. The combination therapy group (Dorz+BYL719) exhibited superior antitumor efficacy compared to the BYL719 group. Conclusions: Our findings indicate that the drug–drug interactions (DDIs) between dorzagliatin and multiple PI3Ki (including WX390 and BYL719) may partially account for the enhanced antitumor efficacy observed in the combination therapy group compared to PI3Ki monotherapy. This interaction may be explained by the inhibition of P-glycoprotein (P-gp) and the pharmacological mechanism of dorzagliatin regarding the activation of insulin regulation.