2ⁿᵈ Edition of the Cancer R&D World Conference 2026

Abstract

Diffuse pleural mesothelioma (DPM) remains a highly aggressive malignancy characterized by loss of tumor suppressors, therapeutic resistance, and an immunosuppressive microenvironment. To address these challenges, we have developed an integrated translational platform that combines microRNA (miRNA)-based therapeutics, biomaterial-enabled delivery systems, and immunomodulatory strategies to enable precision treatment of DPM.

Using unbiased functional screening coupled with patient-derived regulatory network analysis, we identified clinically relevant tumor-suppressive miRNAs that simultaneously target multiple oncogenic pathways. For example, miR-215-5p regulates the MDM2–p53 axis, suppresses cell cycle progression, and enhances apoptosis, demonstrating significant antitumor efficacy, particularly in combination with cisplatin or p53-activating agents. Similarly, miR-206 modulates RTK–RAS–MAPK and CDK pathways, enabling rational combination with CDK4/6 inhibitors to achieve synergistic tumor suppression.

To overcome delivery barriers in mesothelioma, we engineered a peptide-based nanoparticle–hydrogel composite (surface-fill hydrogel, SFH) that enables locoregional, sustained delivery of miRNA. This platform enables uniform coating of pleural surfaces and efficient tumor uptake, resulting in significant tumor regression and improved survival in preclinical models. Importantly, this approach targets residual microscopic disease, a major cause of recurrence.

In addition to directly targeting tumors, we discovered new immune-modulatory agents that trigger immunogenic cell death (ICD), transforming "cold” tumors into immunologically active ones. Combining miRNAs with small molecules that target immune pathways and stimulate anti-tumor immunity by activating dendritic cells and CD8⁺ T-cells significantly improved anti-tumor response when used with immune checkpoint inhibitors.

Collectively, this work establishes a new therapeutic paradigm that integrates miRNA-based multi-target regulation, biomaterial-enabled delivery, and immune reprogramming. These combinatorial strategies offer a scalable, clinically translatable framework for overcoming resistance and improving outcomes in mesothelioma and other solid tumors.