Journal Article Review Epublish
PubMed: 42923368 DOI: 10.3389/fimmu.2026.1965085
Induced mismatch repair deficiency: a hypothesis for the transient and reversible sensitization of mismatch repair-proficient tumors to Immune checkpoint blockade.
Front Immunol 17:1965085
Authors: Paulo P Assumpção, Alessandro Leal, Williams Fernandes Barra, Mário Hiroyuki Hirata, João Vitor Steimbach, Rommel Mario Rodríguez Burbano, Paulo Kassab, Maria Bencivenga, Martín Hernán Bonamino
Affiliations
- Núcleo de Pesquisa Oncológicas (NPO), Universidade Federal do Pará, Belém, Brazil.
- Mass General Brigham Cancer Institute, Harvard Medical School, Boston, MA, United States.
- Faculdade de Ciências Farmacêuticas, Universidade de Sao Paulo, São Paulo, Brazil.
- Programa de Terapia Celular e Gênica, Instituto Nacional de Câncer (INCA), Rio de Janeiro, Brazil.
- Irmandade da Santa Casa de Misericordia de Sao Paulo, São Paulo, Brazil.
- Dept of Surgery, Dentistry, Pediatrics and Gynecology, Verona University, Verona, Italy.
- Vice-presidência de Pesquisa e Coleções Biológicas (VPPCB), Fundação Oswaldo Cruz (FIOCRUZ), Rio de Janeiro, Brazil.
Abstract
Immune checkpoint blockade (ICB) has transformed the treatment landscape of multiple malignancies, producing durable responses and long-term survival in subsets of patients with advanced cancer. However, the clinical benefit of ICB remains largely restricted to tumors displaying pre-existing immune activation, high tumor mutational burden (TMB), or deficient mismatch repair/high microsatellite instability (dMMR/MSI-H) status. In contrast, the vast majority of solid tumors retain proficient mismatch repair (pMMR) function, exhibit limited neoantigen diversity, and frequently display an immunologically "cold" tumor microenvironment, resulting in primary resistance to checkpoint inhibition. Here, we propose the concept of induced mismatch repair deficiency (idMMR), a therapeutic strategy aimed at transiently and reversibly suppressing the core mismatch repair proteins MLH1 and MSH2 in pMMR tumors. We hypothesize that temporary impairment of mismatch repair activity may create a controlled hypermutagenic window during which replication-associated insertion and deletion events accumulate within coding microsatellite regions, with the potential to generate frameshift-derived neoantigens that may enhance tumor immunogenicity. Subsequent restoration of endogenous mismatch repair function would restore basal mutagenesis while preserving newly generated antigenic targets for immune recognition. Unlike constitutive mismatch repair deficiency, idMMR would be pharmacologically controlled and potentially reversible through RNA-based therapeutic approaches. We discuss the biological rationale supporting this hypothesis, the potential immunological consequences of transient mismatch repair suppression, major safety considerations, mechanisms of resistance, and key experimental studies required for validation. Although several critical assumptions remain untested, idMMR may represent a novel framework for converting immunologically cold tumors into ICB-responsive tumors.
MeSH
Dna Mismatch Repair, Microsatellite Repeats, Cold Temperature, Neoplasms, Therapeutics, Microsatellite Instability, Msi-H