Awosika Joy A, Gulley James L, Pastor Danielle M
Gastrointestinal Malignancies Section, Thoracic & GI Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Mol Sci. 2025 May 6;26(9):4394. doi: 10.3390/ijms26094394.
The integrity of the genome is maintained by mismatch repair (MMR) proteins that recognize and repair base mismatches and insertion/deletion errors generated during DNA replication and recombination. A defective MMR system results in genome-wide instability and the progressive accumulation of mutations. Tumors exhibiting deficient MMR (dMMR) and/or high levels of microsatellite instability (termed "microsatellite instability high", or MSI-H) have been shown to possess fundamental differences in clinical, pathological, and molecular characteristics, distinguishing them from their "microsatellite stable" (MSS) counterparts. Molecularly, they are defined by a high mutational burden, genetic instability, and a distinctive immune profile. Their distinct genetic and immunological profiles have made dMMR/MSI-H tumors particularly amenable to treatment with immune checkpoint inhibitors (ICIs). The ongoing development of biomarker-driven therapies and the evaluation of novel combinations of immune-based therapies, with or without the use of conventional cytotoxic treatment regimens, continue to refine treatment strategies with the goals of maximizing therapeutic efficacy and survival outcomes in this distinct patient population. Moreover, the resultant knowledge of the mechanisms by which these features are suspected to render these tumors more responsive, overall, to immunotherapy may provide information regarding the potential optimization of this therapeutic approach in tumors with proficient MMR (pMMR)/MSS tumors.
错配修复（MMR）蛋白可维持基因组的完整性，这些蛋白能够识别并修复DNA复制和重组过程中产生的碱基错配以及插入/缺失错误。有缺陷的MMR系统会导致全基因组不稳定以及突变的逐步积累。已显示，表现出错配修复缺陷（dMMR）和/或微卫星高度不稳定（称为“微卫星不稳定高”，即MSI-H）的肿瘤在临床、病理和分子特征上存在根本差异，使其有别于“微卫星稳定”（MSS）的对应肿瘤。在分子层面，它们的定义是高突变负荷、基因不稳定以及独特的免疫特征。它们独特的基因和免疫特征使得dMMR/MSI-H肿瘤特别适合用免疫检查点抑制剂（ICI）进行治疗。基于生物标志物的疗法的不断发展以及对基于免疫的疗法的新组合的评估，无论是否使用传统的细胞毒性治疗方案，都在继续完善治疗策略，目标是在这一独特的患者群体中最大限度地提高治疗效果和生存结局。此外，关于这些特征被怀疑使这些肿瘤总体上对免疫疗法更敏感的机制的现有知识，可能会为在错配修复功能正常（pMMR）/MSS肿瘤中优化这种治疗方法提供信息。
