恶性周围神经鞘瘤 (MPNST) 是一种侵袭性肉瘤，可能偶发发生，也可能发生在患有遗传综合征 1 型神经纤维瘤病 (NF1) 的患者中。预后很差，因为尺寸过大、复发风险和解剖定位使得手术效果不佳，而且尚无已知的治疗方法。因此，为了设想治疗方案，必须识别能够以有效和选择性的方式受到打击的 MPNST 分子特征。在这里，我们发现 MPNST 表达高水平的糖酵解酶己糖激酶 2 (HK2)，众所周知，当它定位于 MAM（线粒体相关膜）（线粒体和内质网之间的接触位点）时，它可以保护癌细胞免受有害刺激。一种 HK2 靶向肽可将 HK2 从 MAM 中移出，从而迅速诱导 MPNST 细胞大量死亡。在鉴定出 MPNST 微环境中表达的不同基质金属蛋白酶 (MMP) 后，我们设计了 HK2 靶向肽变体，其中包含这些 MMP 的裂解位点，使此类肽可在癌细胞附近激活。我们发现携带 MMP2/9 切割位点的肽在抑制 MPNST 细胞的体外致瘤性和阻碍其在小鼠体内的生长方面是最有效的。我们的数据表明，将 HK2 从 MAM 中分离出来可以为新型抗 MPNST 治疗策略铺平道路，该策略可以灵活地适应肿瘤微环境的蛋白酶表达特征。

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.