Guo Yajing, Zhang Zhifei, Huang Hongxia, Wu Ye, Yin Lixin, Zhou Yang, Ding Feiqing, Hong Sheng, Steinmetz Nicole F, Cai Hui
School of Pharmaceutical Sciences (Shenzhen), Shenzhen Campus of Sun Yat-Sen University, 66 Gongchanglu Road, Guangming District, Shenzhen 518107, China.
Aiiso Yufeng Li Family Department of Chemical and Nano Engineering, Center for Nano Immuno-Engineering, Shu and K.C. Chien and Peter Farrell Collaboratory University of California, San Diego, La Jolla, CA 92093, USA.
Mol Ther. 2025 Apr 2;33(4):1502-1518. doi: 10.1016/j.ymthe.2025.02.042. Epub 2025 Mar 3.
The immunosuppressive microenvironment plays a crucial role in driving and accelerating tumor metastasis. S100A8/A9, produced by myeloid-derived suppressor cells, is a potential therapeutic target for metastatic cancer due to its role in promoting premetastatic niche formation. Previous studies have revealed that the S100A9-targeted peptide (H6, MEWSLEKGYTIK) fused to the Fc region of mouse IgG2b antibodies exhibits antitumor effects; however, the mechanism remains unclear. Here, dual-function peptide nanofibers (H6-Q11) were constructed, consisting of peptide H6 and self-assembly peptide (Q11, QQKFQFQFEQQ), which achieved high avidity for S100A9. In vivo studies showed that H6-Q11 nanofibers significantly prolonged lung retention and inhibited pulmonary metastasis from melanoma and breast cancer without obvious toxicity. Immunological analyses indicated that treatment with H6-Q11 nanofibers decreased the infiltration of immunosuppressive cells while promoting the recruitment of immune effector cells to the lungs, potentially correlated with disturbances of S100A8/A9-NCF1 signaling in the tumor microenvironment. Our findings support a potential clinical application of S100A9-targeted peptide nanofibers as candidate nanomedicine for inhibiting tumor metastasis.
免疫抑制微环境在驱动和加速肿瘤转移中起着关键作用。髓源性抑制细胞产生的S100A8/A9，由于其在促进转移前生态位形成中的作用，是转移性癌症的一个潜在治疗靶点。先前的研究表明，与小鼠IgG2b抗体的Fc区域融合的靶向S100A9的肽（H6，MEWSLEKGYTIK）具有抗肿瘤作用；然而，其机制仍不清楚。在此，构建了由肽H6和自组装肽（Q11，QQKFQFQFEQQ）组成的双功能肽纳米纤维（H6-Q11），其对S100A9具有高亲和力。体内研究表明，H6-Q11纳米纤维显著延长了肺部滞留时间，并抑制了黑色素瘤和乳腺癌的肺转移，且无明显毒性。免疫学分析表明，用H6-Q11纳米纤维治疗可减少免疫抑制细胞的浸润，同时促进免疫效应细胞向肺部募集，这可能与肿瘤微环境中S100A8/A9-NCF1信号的紊乱有关。我们的研究结果支持将靶向S100A9的肽纳米纤维作为抑制肿瘤转移的候选纳米药物的潜在临床应用。
