XPANTHER

Pancreatic ductal adenocarcinoma (PDAC) is recognized as an immunologically cold tumor due to several distinct characteristics that collectively hinder effective immune response against the cancer cells. Unlike "hot" tumors, which typically exhibit high levels of immune cell infiltration and response, PDAC creates a hostile environment that evades immune surveillance and therapy. The tumor microenvironment (TME) is hypoxic and immunosuppressive, further impairing immune cell function. PDAC also has a low mutational burden and insufficient neoantigens, reducing its susceptibility to immune checkpoint blockade therapies.

Hyperthermic radiotherapy (HRT) is an advanced cancer treatment approach that combines the use of hyperthermia (therapeutic heating of tumor tissues) with radiotherapy. This combination enhances the effectiveness of traditional radiotherapy and has shown promise in improving cancer treatment outcomes. One of the key mechanisms through which HRT exerts its effects is the generation of neoantigens, which play a crucial role in eliciting robust antitumor immune responses. Cancer treatment based on nanoparticles (NPs), while promising for delivering heat and reaching the tumor site due to their small size, faces challenges. Inadequate release of therapeutic agents limits efficacy and the TME's complexity impedes precise targeting, affecting selective delivery. The lack of standardized protocols for combining NP-based treatments with existing therapies hinders clinical integration.

The XPANTHER project aims to integrate hyperthermic radiotherapy with innovative NP-based treatments in relevant in vitro models recapitulating the human TME. It involves examining oxidative ion release and cascades from efficient heaters (molybdenum oxide and iron oxide NPs) and radiosensitizers (hafnium oxide NPs) in tumoroid and tumor-on-a-chip (ToC) models adhering to 3R (Replace, Reduce, Refine) rules. This research explores physical treatments and enables advanced in operando physical characterizations using techniques like synchrotron radiation-based X-ray absorption spectroscopy.

The project comprises three modules: 1) to turn immunologically cold pancreatic tumors into hot tumors through combined therapy based on hyperthermic-radiotherapy, 2) to use novel NPs as efficient releasers of metal ions triggering ROS for efficient radio- and thermal therapies, 3) to target hypoxic tumors on tumoroid and ToC models based on PDAC that could benefit from multimodal nanotherapies, associated with hypoxia-related radiation resistance. The goal is to advance NP-based treatments, improving therapeutic advantages over conventional methods for precise, personalized cancer treatment. Expected outcomes include enhanced patient quality of life and reduced healthcare costs, bringing us closer to realizing the full potential of nanotherapies in the clinical setting.