# Mesenchymal Stem Cell-Derived Exosomes Reprogram Chemosensitivity Pathways in Cervical Cancer Spheroids

## TL;DR

This study shows that exosomes from mesenchymal stem cells can change how cervical cancer cells respond to chemotherapy, depending on the cell type and drug used.

## Contribution

The study reveals cell-type and drug-specific effects of MSC-exosomes on chemotherapy response in cervical cancer spheroids.

## Key findings

- MSC-exosomes altered spheroid responses to paclitaxel in combination with cisplatin or carboplatin.
- MSC-exosome pretreatment enhanced chemotherapy-induced cytotoxicity in HeLa spheroids.
- SiHa spheroids showed selective responses to MSC-exosome pretreatment depending on the drug combination.

## Abstract

Cervical cancer (CC) remains a major global health challenge due to chemotherapy resistance and recurrence. Mesenchymal stem cell-derived exosomes (MSC-exosomes) have dual roles, as they can act as therapeutic agents and contribute to chemoresistance. However, their role in response to chemotherapy in CC remains unclear. Therefore, our study investigated the effects of MSC-exosome pretreatment on chemotherapy sensitivity using three-dimensional spheroid models generated from HeLa and SiHa CC cell lines. Proteomic profiling of MSC-exosomes identified key proteins, including ANXA1, ANXA2, EEF2, LGALS1, and PKM2, associated with tumor regeneration and chemotherapy response. MSC-exosomes exhibited context-dependent effects in both chemoresistance and chemosensitization by modulating drug efflux, metabolic reprogramming, stress adaptation, apoptosis, DNA damage response, and integrin-mediated signaling. MSC-exosome pretreatment altered spheroid responses to paclitaxel in combination with cisplatin or carboplatin. MSC-exosomes significantly enhanced chemotherapy-induced cytotoxicity in HeLa spheroids, as evidenced by reduced cell viability, increased caspase activity, and upregulation of the pro-apoptotic marker Bax. In contrast, SiHa spheroids represented selective responses: MSC-exosome pretreatment did not enhance sensitivity to paclitaxel–cisplatin but improved responsiveness to paclitaxel–carboplatin, particularly within the spheroid core. Overall, MSC-exosome pretreatment exerts cell type and drug-specific effects in CC spheroids, supporting their potential to modulate chemotherapy response.