HER2-Targeted Nanoliposome Therapy Activates Immune Response by Converting Cold to Hot Breast Tumors.

IF 2.8 4区 医学 Q3 ONCOLOGY
Technology in Cancer Research & Treatment Pub Date : 2025-01-01 Epub Date: 2025-07-10 DOI:10.1177/15330338251356387
Quan Sun, Ying Zhu, Dongli Zhao, Lili Yang, Siyu Zhang, Changxin Huang
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引用次数: 0

Abstract

IntroductionHER2-positive breast cancer, accounting for 15%-20% of cases, remains challenging due to therapy resistance and immunosuppressive "cold tumor" microenvironments. Current strategies combining immunotherapy with chemotherapy or radiotherapy often face toxicity limitations. To address this, we developed HER2-targeted nanoliposomes co-delivering viral peptides and the STING agonist diABZI, aiming to convert cold tumors into immunologically active "hot tumors" by enhancing antigen spreading and immune recognition.MethodsViral peptides with high Human Leukocyte Antigen-A2 affinity were selected using NetMHCpan-4.1/4.0 and incorporated into nanoliposomes via thin-film dispersion. Trastuzumab F(ab')2 fragments were conjugated for HER2-specific targeting. Nanoliposomes were characterized for size, stability, encapsulation efficiency (HPLC), and in vitro release. Immune efficacy was assessed via ELISPOT, flow cytometry (CD3+/CD8+/NK cells), and TCR β sequencing in HER2+ SK-BR-3 and HER2- MCF-7 cells. Cytotoxicity and cellular uptake were evaluated using CCK-8 assays and fluorescence imaging.ResultsThe nanoliposomes exhibited uniform size (∼70 nm), stability (5% size variation over 25 days), and high encapsulation efficiency (75.5% for peptides). Targeted delivery to SK-BR-3 cells peaked at 60 µL (P < .05), with sustained release of peptides (52% at 48 h) and diABZI (46.2%). In HER2+ cells, nanoliposomes synergistically enhanced IFN-γ (2.5-fold, P < .01) and granzyme B (3-fold, P < .05) secretion, overcoming antagonism seen with free agents. Flow cytometry revealed dominant CD8+ T-cell infiltration (50.9% vs 0.67% in controls) and expanded NK/NKT populations. TCR β sequencing showed increased clonotype diversity (60,915 vs 57 574 clones) and reduced clonal dominance, indicating broadened antigen recognition.ConclusionOur HER2-targeted nanoliposomes effectively reprogrammed cold tumors by dual activation of innate (STING pathway) and adaptive (viral peptide-driven TCR diversity) immunity. The platform demonstrated robust targeting, safety, and immune activation, offering a promising strategy to overcome immunotherapy resistance. Future studies will validate in vivo efficacy and explore adaptations for other cold tumors via alternative targeting ligands.

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靶向her2的纳米脂质体治疗通过将冷乳腺癌转化为热乳腺癌激活免疫反应。
her2阳性乳腺癌占病例的15%-20%,由于治疗耐药和免疫抑制的“冷肿瘤”微环境,仍然具有挑战性。目前将免疫治疗与化疗或放疗相结合的策略往往面临毒性限制。为了解决这个问题,我们开发了her2靶向纳米脂质体,共同递送病毒肽和STING激动剂diABZI,旨在通过增强抗原扩散和免疫识别将冷肿瘤转化为具有免疫活性的“热肿瘤”。方法采用NetMHCpan-4.1/4.0筛选具有高亲和力的病毒肽,通过薄膜分散将其整合到纳米脂质体中。曲妥珠单抗F(ab’)2片段被偶联用于her2特异性靶向。对纳米脂质体的大小、稳定性、包封效率和体外释放度进行了表征。通过ELISPOT、流式细胞术(CD3+/CD8+/NK细胞)和TCR β测序对HER2+ SK-BR-3和HER2- MCF-7细胞进行免疫效果评估。采用CCK-8检测和荧光成像评估细胞毒性和细胞摄取。结果纳米脂质体尺寸均匀(~ 70 nm),稳定性好(25 d内大小变化5%),包封率高(多肽包封率为75.5%)。靶向递送至SK-BR-3细胞60µL时达到峰值(P +细胞),纳米脂质体协同增强IFN-γ(2.5倍),P + t细胞浸润(50.9% vs 0.67%对照)并扩大NK/NKT群体。TCR β测序显示克隆型多样性增加(60,915对57 574个克隆),克隆优势度降低,表明抗原识别范围扩大。结论her2靶向纳米脂质体通过双重激活先天性(STING途径)和适应性(病毒肽驱动的TCR多样性)免疫,有效地对冷肿瘤进行了重编程。该平台表现出强大的靶向性、安全性和免疫激活性,为克服免疫治疗耐药性提供了一种有希望的策略。未来的研究将验证其体内有效性,并通过替代靶向配体探索对其他冷肿瘤的适应性。
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来源期刊
CiteScore
4.40
自引率
0.00%
发文量
202
审稿时长
2 months
期刊介绍: Technology in Cancer Research & Treatment (TCRT) is a JCR-ranked, broad-spectrum, open access, peer-reviewed publication whose aim is to provide researchers and clinicians with a platform to share and discuss developments in the prevention, diagnosis, treatment, and monitoring of cancer.
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