Mesenchymal stem cell-derived exosomes reprogram chemosensitivity pathways in cervical cancer spheroids

ABSTRACT: Cervical cancer (CC) remains a global health challenge, with chemotherapy resistance and tumor recurrence limiting treatment success. Our study investigated the effects of mesenchymal stem cell-derived exosome (MSC-Exos) pretreatment on chemotherapy sensitivity in 3D spheroids generated from HeLa and SiHa CC cell lines. Proteomic profiling of MSC-Exos revealed key proteins, including ANXA1, ANXA2, EF2, LGALS1, and PKM2, with potential roles in tumor regeneration and chemosensitization. Our findings highlight the context-dependent nature of MSC-Exo activity: while they may promote chemoresistance via drug efflux, metabolic reprogramming, and stress adaptation, they can also enhance chemosensitivity by modulating apoptosis, DNA damage response, and integrin-mediated signaling pathways. Functionally, spheroids pretreated with MSC-Exos exhibited altered responses to paclitaxel in combination with either cisplatin or carboplatin, underscoring the potential of MSC-Exos as modulators of chemotherapy response in CC. In HeLa spheroids, pretreatment with MSC-Exo significantly enhanced chemotherapy-induced cytotoxicity, evidenced by decreased cell viability, increased caspase activity, and upregulation of pro-apoptotic markers such as Bax, suggesting sensitization to apoptosis via chemotherapy. Conversely, SiHa spheroids exhibited variable responses. Although MSC-Exo pretreatment did not sensitize SiHa spheroids to paclitaxel-cisplatin, it improved responsiveness to paclitaxel–carboplatin, particularly in the spheroid core. Molecular analysis revealed upregulated SOX2 expression in SiHa spheroids, indicating partial activation of stemness pathways without full acquisition of a cancer stem cell phenotype. Overall, our findings reveal that MSC-Exo pretreatment exerts cell type- and drug-specific effects in CC spheroids. They enhance chemotherapeutic efficacy in HeLa spheroids and selectively alter drug sensitivity in more resistant SiHa spheroids. The results, therefore, represent promising candidates for engineered exosome-based adjuvant therapies in CC.

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Raphatphorn Navakanitworakul 

PROVIDER: PXD069108 | JPOST Repository | Fri Apr 10 00:00:00 BST 2026

REPOSITORIES: jPOST