1.1 Research and technological achievements
The MMSCancer project is progressing according to plan, achieving significant advances toward modulating tumor mechanics through mechanotherapeutic and ultrasound sonopermeation to enhance nano-immunotherapy.
Research Objective 1 was completed, demonstrating that ketotifen effectively modulates tissue stiffness, improving perfusion and drug delivery in pancreatic and sarcoma models. Ongoing work focuses on:
(i) RO2: Testing sonopermeation’s ability to improve perfusion and delivery,
(ii) RO3: Developing and validating a biomechanical model to optimize the combination of mechanotherapy and sonopermeation.
Implementation of RO4, testing the combined strategy on therapy efficacy, is planned after month 36.
Ten research articles have been published, including in Journal of Controlled Release and Neoplasia.
A key achievement is demonstrating that combining ultrasound-mediated sonopermeation with stroma normalization enhances nano-immunotherapy efficacy in various cancers. This provides the first preclinical evidence that transient, non-invasive mechanical modulation can synergize with immunotherapy. Optimized sonopermetation parameters normalized tumor vasculature and extracellular matrix, improving nanoparticle penetration, immune cell infiltration, and tumor regression, validating the MMSCancer approach across models.
Complementary computational and experimental work produced a multiscale model predicting the dynamics of mechanical forces, perfusion, and drug transport. It identified optimal regimens for stroma normalization and ultrasound exposure, minimizing tissue damage while maximizing drug delivery. Integration of in vivo and in silico data provided a mechanistic basis for rational therapy optimization and clinical translation.
Overall, MMSCancer has established a robust experimental–computational platform integrating mechanotherapy and sonopermeation to normalize tumor pathophysiology, restore perfusion, and potentiate nano-immunotherapy—a major advance in tumor mechanobiology and therapeutic transport.
________________________________________
1.2 Novel methodologies, inter-disciplinary developments and knowledge transfer
A major conceptual advance is the combined use of mechanotherapeutics and sonopermeation as a unified, clinically transferable strategy using already approved agents. A multiscale modeling framework was also established, integrating mechanics, fluid dynamics, and immune simulations to predict and optimize treatment regimens.
Methodological progress includes image-guided quantification of tissue biomechanics using shear wave elastography, contrast-enhanced ultrasound, and fluorescent nanoparticles to monitor stiffness, perfusion, and nanoparticle distribution. These tools validate mechanical normalization and provide translational biomarkers for therapy monitoring.
The project has fostered strong interdisciplinary collaboration across physics, engineering, and biology, enabling training of young researchers in mechanobiology, ultrasound engineering, and modeling. Knowledge transfer is ensured through joint publications, conference presentations, and open-access sharing of data and computational tools.
________________________________________
1.3 Most significant achievements
Five key publications highlight the project’s impact:
1. Mpekris F. et al. (2024) Neoplasia, 51:100990.
2. Mpekris F. et al. (2024) Cell Reports Medicine, 5(7):101626.
3. Koutsi M. et al. (2025) PLoS Comput. Biol., 21(9):e1012676.
4. Koutsi M. et al. (2025) Frontiers in Drug Delivery, 5:1549098.
5. Neophytou C. et al. (2025) J. Controlled Release, 382:113722.
Results were presented at:
• CRS Annual Meeting 2024 (Bologna)
• ESMI 2025 (Bilbao)
• TMCS 2024 (Paphos)
• WCCRT 2025 (Vienna)
