Induced mismatch repair deficiency: a hypothesis for the transient and reversible sensitization of mismatch repair-proficient tumors to Immune checkpoint blockade
7 affiliations
- 1Núcleo de Pesquisa Oncológicas (NPO), Universidade Federal do Pará
- 2Mass General Brigham Cancer Institute, Harvard Medical School
- 3Faculdade de Ciências Farmacêuticas, Universidade de Sao Paulo
- 4Programa de Terapia Celular e Gênica, Instituto Nacional de Câncer (INCA)
- 5Irmandade da Santa Casa de Misericordia de Sao Paulo
- 6Dept of Surgery, Dentistry, Pediatrics and Gynecology, Verona University
- 7Vice-presidência de Pesquisa e Coleções Biológicas (VPPCB), Fundação Oswaldo Cruz (FIOCRUZ)
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.
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BibTeX
@article{assumpcao2026induced,
title = {{Induced mismatch repair deficiency: a hypothesis for the transient and reversible sensitization of mismatch repair-proficient tumors to Immune checkpoint blockade}},
author = {Paulo P. Assumpção and Alessandro Leal and Williams Fernandes Barra and Mário Hiroyuki Hirata and João Vitor Steimbach and Rommel Mario Rodríguez Burbano and Paulo Kassab and Maria Bencivenga and Martín Hernán Bonamino and P\&D consortium},
journal = {Frontiers in Immunology},
year = {2026},
month = oct,
doi = {10.3389/fimmu.2026.1965085},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1965085/full},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Induced mismatch repair deficiency: a hypothesis for the transient and reversible sensitization of mismatch repair-proficient tumors to Immune checkpoint blockade
AU - Paulo P. Assumpção
AU - Alessandro Leal
AU - Williams Fernandes Barra
AU - Mário Hiroyuki Hirata
AU - João Vitor Steimbach
AU - Rommel Mario Rodríguez Burbano
AU - Paulo Kassab
AU - Maria Bencivenga
AU - Martín Hernán Bonamino
AU - P&D consortium
PY - 2026
DA - 2026/10/08
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.1965085
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1965085/full
AB - 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.
SN - 1664-3224
ER -