dMMR/MSI-H转移性结直肠癌免疫治疗耐药机制及耐药后治疗进展

doi:10.3760/cma.j.cn371439-20250417-00101

摘要/Abstract

摘要：

错配修复缺陷和（或）微卫星高度不稳定性（dMMR/MSI-H）转移性结直肠癌（CRC）因高肿瘤突变负荷和新抗原富集对免疫检查点抑制剂具有较高的敏感性，但仍有45%~60%的患者存在原发或获得性耐药。其耐药机制复杂，涉及肿瘤微环境异质性、多重免疫检查点共表达、致癌通路异常激活、代谢失调、肠道菌群失衡、HLA-Ⅰ类分子缺陷及表观遗传调控等。目前针对逆转免疫治疗耐药的策略包括免疫联合疗法、个性化新抗原疫苗、肠道菌群移植、表观遗传干预及免疫细胞过继疗法等。进一步分析dMMR/MSI-H转移性CRC免疫治疗耐药的潜在机制以及目前克服免疫治疗耐药的策略，可为逆转此类患者免疫治疗耐药提供理论依据。

关键词: 结直肠肿瘤, 微卫星不稳定性, 免疫检查点抑制剂, 抗药性，肿瘤

Abstract:

Deficient mismatch repair/microsatellite instability-high （dMMR/MSI-H） metastatic colorectal cancer （CRC） is highly sensitive to immune checkpoint inhibitors due to the high tumor mutation load and neoantigen enrichment. However， 45%-60% of patients exhibit primary or acquired immunotherapy resistance. The mechanisms underlying this resistance are complex， involving tumor microenvironment heterogeneity， co-expression of multiple immune checkpoints， aberrant activation of oncogenic pathways， metabolic dysregulation， intestinal microbiota imbalance， HLA-Ⅰ molecule defects， and epigenetic regulation. Current strategies aimed at reversing immunotherapy resistance include combination immunotherapies， personalized neoantigen vaccines， intestinal microbiota transplantation， epigenetic interventions， and adoptive immune cell therapies. Further analysis of the potential mechanisms of immune therapy resistance in dMMR/MSI-H metastatic CRC， and the exploration of current strategies to overcome resistance can provide a theoretical basis for reversing the immunotherapy resistance in such patients.

Key words: Colorectal neoplasms, Microsatellite instability, Immune checkpoint inhibitors, Drug resistance， neoplasm

海亚楠, 鲍文芳, 申屠航笑, 陈敬德. dMMR/MSI-H转移性结直肠癌免疫治疗耐药机制及耐药后治疗进展[J]. 国际肿瘤学杂志, 2025, 52(9): 598-602.

Hai Yanan, Bao Wenfang, Shentu Hangxiao, Chen Jingde. Mechanism of immunotherapy resistance and the progress of post-resistance treatment for dMMR/MSI-H metastatic colorectal cancer[J]. Journal of International Oncology, 2025, 52(9): 598-602.

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