Harnessing tumor acidosis and immunogenic ferroptosis for an innovative treatment of peritoneal carcinomatosis with PUFA-loaded nanovesicles

Different cancers can disseminate into the peritoneal cavity. The bad prognosis for patients with peritoneal tumors mainly arises from the progressive resistance of cancer cells to die in response to conventional therapy according to specific pathways such as apoptosis. Killing cancer cells through other modalities is therefore of utmost interest. Ferroptosis is a recently discovered alternative type of cell death based on the oxidation of specific fatty acids, the well-known omega-3 and -6 polyunsaturated fatty acids (PUFA). Oxidized PUFA alter cell membrane integrity and generate toxic signals that induce an immune response against the whole tumor.

However, dietary PUFA leads to insufficient concentrations in human tumors to profoundly impact cancer progression. Here, we aim to load PUFA into nanovehicles and inject them directly into the peritoneum to bypass the systemic circulation and efficiently reach peritoneal tumors. To further increase PUFA delivery specificity, we will use pH-sensitive nanovehicles that will only release PUFA in the acidic tumor compartment that is particularly prone to capture fatty acids. We will also use drugs to increase PUFA availability (by preventing storage and metabolization) and photodynamic therapy to enhance their oxidability. This interdisciplinary approach combined with tumor spheroids, mouse tumor models and patient-derived tumor organoids will lead to development of efficient targeted strategies against peritoneal carcinomatosis.