High microsatellite instability (MSI-H) derives from genomic hypermutability due to deficient mismatch repair function. Colorectal (CRC) and endometrial cancers (EC) are the tumor types that more often present MSI-H. Anti-PD(L)-1 antibodies have been demonstrated to be agnostically effective in patients with MSI-H cancer, but 50–60% of them do not respond to single-agent treatment, highlighting the necessity of expanding their treatment opportunities. Ipilimumab (anti-CTLA4) is the only immune checkpoint inhibitor (ICI) non-targeting PD(L)-1 that has been approved so far by the FDA for MSI-H cancer, namely, CRC in combination with nivolumab. Anti-TIM3 antibody LY3321367 showed interesting clinical activity in combination with anti-PDL-1 antibody in patients with MSI-H cancer not previously treated with anti-PD(L)-1. In contrast, no clinical evidence is available for anti-LAG3, anti-TIGIT, anti-BTLA, anti-ICOS and anti-IDO1 antibodies in MSI-H cancers, but clinical trials are ongoing. Other immunotherapeutic strategies under study for MSI-H cancers include vaccines, systemic immunomodulators, STING agonists, PKM2 activators, T-cell immunotherapy, LAIR-1 immunosuppression reversal, IL5 superagonists, oncolytic viruses and IL12 partial agonists. In conclusion, several combination therapies of ICIs and novel strategies are emerging and may revolutionize the treatment paradigm of MSI-H patients in the future. A huge effort will be necessary to find reliable immune biomarkers to personalize therapeutical decisions.
高度微卫星不稳定性（MSI-H）源于错配修复功能缺陷导致的基因组高突变性。结直肠癌（CRC）和子宫内膜癌（EC）是最常出现MSI-H的肿瘤类型。抗PD(L)-1抗体已被证明对MSI-H癌症患者具有广谱疗效，但其中50-60%的患者对单药治疗无反应，这凸显了拓展其治疗选择的必要性。伊匹木单抗（抗CTLA4）是目前FDA批准用于MSI-H癌症（即与纳武利尤单抗联合治疗结直肠癌）的唯一非靶向PD(L)-1的免疫检查点抑制剂（ICI）。抗TIM3抗体LY3321367与抗PDL-1抗体联合用于既往未接受抗PD(L)-1治疗的MSI-H癌症患者时，显示出具有前景的临床活性。相比之下，抗LAG3、抗TIGIT、抗BTLA、抗ICOS和抗IDO1抗体在MSI-H癌症中尚无临床证据，但相关临床试验正在进行中。正在研究的其他MSI-H癌症免疫治疗策略包括疫苗、系统性免疫调节剂、STING激动剂、PKM2激活剂、T细胞免疫疗法、LAIR-1免疫抑制逆转剂、IL5超激动剂、溶瘤病毒和IL12部分激动剂。总之，多种ICI联合疗法及新型策略正在涌现，未来可能彻底改变MSI-H患者的治疗模式。未来需要付出巨大努力寻找可靠的免疫生物标志物，以实现治疗决策的个体化。
肿瘤(癌症)患者之家