Jin Xiangyuan, Wuyun Tanghesi, Zhang Yu, Wang Xiaohong, Zhao Ling
Department of Thoracic Surgery, Harbin Medical University Cancer Hospital, Harbin, 150081, China.
The Second Department of Respiratory, Harbin Medical University Cancer Hospital, No. 150, Haping Road, Nangang District, Harbin, 150081, Heilongjiang, China.
J Nanobiotechnology. 2025 Jun 13;23(1):443. doi: 10.1186/s12951-025-03456-1.
Non-small cell lung cancer (NSCLC) remains a major global health challenge, with limited therapeutic success due to drug resistance and the immunosuppressive tumor microenvironment (TME). This study explores a novel strategy to overcome acquired resistance to immunotherapy in phosphoinositide 3-kinase (PI3K)-mutated NSCLC. Tumor-derived exosomes (T-exo) were modified with the tumor-targeting peptide TMTP1 and loaded with Ginsenoside Rb1 (Rb1) via electroporation to develop peptide-modified Rb1@T-exo. This innovative delivery system demonstrated enhanced tumor-targeting ability and improved stability and bioavailability of Rb1. Both in vitro and in vivo experiments revealed that Rb1@T-exo effectively suppressed tumor growth and metastasis, significantly inhibited the PI3K/AKT/mTOR signaling pathway, and remodeled the immune microenvironment by promoting M1 macrophage polarization and enhancing CD8 T cell proliferation and cytotoxicity. Transcriptomic and bioinformatic analyses identified key differentially expressed genes (DEGs) and pathways associated with resistance reversal, including the PI3K/AKT/mTOR and PD-1/PD-L1 pathways. Moreover, Rb1@T-exo synergized with immune checkpoint blockade therapy, demonstrating potential as a dual therapeutic approach. This study highlights the potential of peptide-modified Rb1@T-exo as a targeted therapeutic platform for overcoming immunotherapy resistance in PI3K-mutated NSCLC and provides a promising direction for future anti-tumor therapies.
非小细胞肺癌（NSCLC）仍然是一项重大的全球健康挑战，由于耐药性和免疫抑制性肿瘤微环境（TME），治疗成功率有限。本研究探索了一种新策略，以克服磷酸肌醇3激酶（PI3K）突变的NSCLC对免疫疗法的获得性耐药。用肿瘤靶向肽TMTP1修饰肿瘤来源的外泌体（T-exo），并通过电穿孔加载人参皂苷Rb1（Rb1），以开发肽修饰的Rb1@T-exo。这种创新的递送系统显示出增强的肿瘤靶向能力，并提高了Rb1的稳定性和生物利用度。体外和体内实验均表明，Rb1@T-exo有效抑制肿瘤生长和转移，显著抑制PI3K/AKT/mTOR信号通路，并通过促进M1巨噬细胞极化和增强CD8 T细胞增殖及细胞毒性来重塑免疫微环境。转录组学和生物信息学分析确定了与耐药逆转相关的关键差异表达基因（DEG）和通路，包括PI3K/AKT/mTOR和PD-1/PD-L1通路。此外，Rb1@T-exo与免疫检查点阻断疗法协同作用，显示出作为双重治疗方法的潜力。本研究突出了肽修饰的Rb1@T-exo作为克服PI3K突变NSCLC免疫治疗耐药性的靶向治疗平台的潜力，并为未来的抗肿瘤治疗提供了一个有前景的方向。
