Regulatory T‐cells (Tregs) play an important role in tumor immunosuppressive network, thus Tregs‐targeted strategy is expected to enhance antitumor immunity and improve the effect of immunotherapy. Short peptide P60 can bind to the forkhead box protein P3 (Foxp3), a crucial transcriptional regulator for the development and inhibitory function of Tregs, and inhibit Foxp3 nuclear translocation in Tregs. However, its treatment effect in cancer is limited due to nonspecificity. Therefore, realizing the specific delivery of P60 in tumor microenvironment will greatly facilitate its Treg‐suppressing effect for tumor therapeutics. Herein, utilizing the unique matrix metallase protease 2/9 (MMP2/9) overexpressing feature in tumor tissues, a fusion protein 6(P60‐MMPs) containing six segments of P60 linked by MMP2/9‐sensitive peptides is constructed for antitumor targeting immunotherapy. The fusion protein 6(P60‐MMPs) specifically degrades into short peptide P60 in tumor, and then binds to Foxp3 to inhibit Foxp3 nuclear translocation in Tregs, thus impairing Tregs’ activity. This fusion protein efficiently inhibits murine breast cancer 4T1 transplanted tumor growth and decreases lung metastasis through down‐regulating tumor‐infiltrated Tregs and up‐regulating CD8⁺ T cells in tumor tissue. The study develops a Treg‐targeted anticancer fusion protein with effective therapeutic activity, suggesting its potential in clinical translation.

中文翻译：

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MMP2 / 9敏感短肽链接的P60融合蛋白6（P60-MMPs）靶向抑制Foxp3，以增强抗肿瘤免疫力。

调节性T细胞（Tregs）在肿瘤免疫抑制网络中起着重要作用，因此以Tregs为靶点的策略有望增强抗肿瘤免疫力并提高免疫疗法的效果。短肽P60可以与叉头盒蛋白P3（Foxp3）结合，后者是Tregs的发育和抑制功能的关键转录调节因子，并抑制Foxp3在Tregs中的核易位。然而，由于非特异性，其在癌症中的治疗作用受到限制。因此，实现P60在肿瘤微环境中的特异性递送将极大地促进其对肿瘤治疗剂的Treg抑制作用。在此，利用肿瘤组织中独特的基质金属蛋白酶2/9（MMP2 / 9）过表达功能，构建了包含MMP2 / 9敏感肽连接的P60六段的融合蛋白6（P60-MMPs），用于抗肿瘤靶向免疫治疗。融合蛋白6（P60-MMPs）在肿瘤中特异性降解为短肽P60，然后与Foxp3结合以抑制Treg中的Foxp3核易位，从而削弱Treg的活性。这种融合蛋白可通过下调肿瘤浸润的Tregs和上调CD8来有效抑制小鼠乳腺癌4T1移植肿瘤的生长并减少肺转移肿瘤组织中的⁺ T细胞。这项研究开发了一种靶向Treg的抗癌融合蛋白，具有有效的治疗活性，表明其在临床翻译中的潜力。