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Immunity under Pressure: Mapping Compression Driven Tumor–Immune Rewiring to Potentiate Immunotherapy in Pancreatic Cancer

Obiettivo

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a dense, stiff stroma and elevated compressive forces within its tumor microenvironment, yet mechanical abnormalities are overlooked in treatment decisions. My prior work has shown that compression reprograms PDAC cells, activating pathways that drive migration and chemotherapy resistance. While chemotherapy remains the standard of care, its toxicity and limited survival benefits highlight the need for alternatives, such as immunotherapies, which harness the immune system but show minimal efficacy in PDAC. My preliminary data indicate that compression drives immune evasion, metabolic rewiring, and an immunosuppressive niche, yet the mechanisms linking compressive stress to immunotherapy failure remain unresolved. MechanoImmunoMap integrates experimental and computational approaches to map how compressive forces reprogram tumor-immune interactions. Bioengineered 3D coculture models of tumor and immune cells under tunable compression, combined with multiomic profiling and mathematical modeling, will identify mechano-immunoregulatory pathways. These pathways will be validated in vivo using mechanically characterized orthotopic PDAC models to build a comprehensive map of compression-driven tumor-immune rewiring. Linking mapped pathways to therapeutic target databases will identify drugs capable of counteracting compression-induced resistance. Prioritized drug candidates will be tested in vitro with immunotherapy and validated in vivo to deliver novel combination therapies that potentiate immunotherapy. Finally, machine learning models will be employed to link compressive stress with multiomic tumor-immune profiling, establishing an engineering framework for immunotherapy response prediction. MechanoImmunoMap transforms compressive forces from a neglected barrier into a biomarker and therapeutic target, laying the foundation for mechanically informed precision oncology in PDAC and other solid tumors.

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HORIZON-ERC - HORIZON ERC Grants

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Istituzione ospitante

UNIVERSITY OF CYPRUS
Contributo netto dell'UE
€ 1 500 000,00
Indirizzo
AVENUE PANEPISTIMIOU 2109 AGLANTZI
1678 Nicosia
Cipro
Regione
Κύπρος Κύπρος Κύπρος
Tipo di attività
Higher or Secondary Education Establishments
Collegamenti
Costo totale
€ 1 500 000,00

Beneficiari (1)