The battle against colorectal cancer (CRC), particularly peritoneal metastases (PM), necessitates innovative treatments beyond standard chemotherapy, surgery, and HIPEC, as these have shown limited success in preventing recurrence. With approximately 25% of CRC patients developing PM, often exhibiting a mesenchymal phenotype with poor survival rates, there is an urgent need for therapeutic advancements. The project aims to harness the body´s immune system to fight cancer by converting an immunosuppressive environment into an immune-responsive one. The strategy involves a single post-surgical application of a supramolecular nanofiber hydrogel into the peritoneum to deliver a sustained triple combination therapy.

We hypothesize that a supramolecular nanofiber hydrogel can release a sequential, synergistic wave of treatments: first, radiotherapeutic nanoparticles to induce immunogenic cell death and expose tumor antigens; second, a TLR 7/8 agonist to activate antigen-presenting cells, prompting T cell responses; and third, immune checkpoint blockers to reverse immune suppression and clear remaining cancer cells. The hydrogel, formulated from ureidopyrimidinone (UPy)-PEG polymers, can be loaded with these agents and engineered to release drugs in three phases, targeting cancer cell eradication, innate immune activation, and T cell-mediated tumor destruction.

The project´s sub-objectives include the design of hydrogels to encapsulate radiotherapeutic nanoparticles and TLR7/8 agonists, co-formulation with immune checkpoint blockers, and administration via spraying into the peritoneal cavity post-surgery. The efficacy of this approach will be evaluated in preclinical mouse models to elucidate the underlying therapeutic mechanisms. This project not only aims to prevent PM recurrence but also to contribute to the broader research community by offering a novel immunotherapeutic strategy, potentially revolutionizing CRC treatment and impacting societal health outcomes.