Mutagenic chemotherapy and inhibition of mismatch repair as a strategy to boost anti-tumor immune response

Objective

In colorectal cancer (CRC), the efficacy of immunotherapy is currently limited to a small subgroup of tumors characterized by mismatch repair (MMR) deficiency. Conversely, little or no clinical benefit has been shown in the large majority of CRCs with MMR proficiency, which are accordingly defined as immune-cold tumors. Determining how to turn an immune-cold into a hot (immunotherapy responsive) tumor remains a major scientific challenge and an unmet clinical need. Building on our recent demonstration that cytotoxic agents can increase tumor mutational burden and induce an immunogenic MMR deficient (MMRd)-like profile in preclinical CRC models, we devised CHIMERA as an ERC-2025-PoC initiative. CHIMERA leverages a validated in vitro and in vivo workflow to assess a first-in-class MMR inhibitor in combination with rationally selected cytotoxic agents, with the objective of converting MMR proficient (MMRp) cold tumors into an immunotherapy-responsive hot state. The project translates concepts generated within the ERC-ADG into a development program that integrates available drugs with novel molecules, thereby extending immunotherapy applicability beyond the current MMRd subgroup. Ultimately, CHIMERA is designed to consolidate proof-of-concept evidence for an innovative therapeutic strategy, laying the foundation for subsequent clinical testing and broader patient benefit in immuno-oncology.