CELL INTELLIGENCE · 肿瘤细胞治疗研究

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靶向 PD-1 和 TGF-β通路的酶响应性纳米载体逆转免疫治疗耐药并产生强效治疗效果

英文原题：Enzymatically responsive nanocarriers targeting PD-1 and TGF-β pathways reverse immunotherapeutic resistance and elicit robust therapeutic efficacy.

查看英文原题

Enzymatically responsive nanocarriers targeting PD-1 and TGF-β pathways reverse immunotherapeutic resistance and elicit robust therapeutic efficacy.

PubMed 2025/02/19（内容时间） J Nanobiotechnology Q1 · IF 15（JCR 2025）

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肺癌地区：中国
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中文摘要

免疫检查点抑制剂（ICIs）已彻底改变肺癌治疗格局，但耐药仍是难题。PD-1/PD-L1与TGF-β的双重抑制展现出前景，却面临疗效有限和全身毒性的问题。我们开发了明胶酶响应性纳米颗粒（GPNPs），递送抗PD-1抗体（αPD-1）和TGF-β受体I抑制剂galunisertib（Gal）。GPNPs有效抑制肿瘤进展，且未观察到副作用。通过流式细胞术进行的免疫分析显示，活化和耗竭的TIL（肿瘤浸润淋巴细胞）（TILs）及巨噬细胞均被大量募集。转录组分析表明细胞外基质受到调控，并得到胶原沉积和αSMA表达减少的支持。命运图谱分析证明Pdgfrα+成纤维细胞向αSMA肌成纤维细胞的转变被减弱，可能逆转“免疫排斥”状态。本研究验证了GPNPs作为一种有前景的肺癌免疫治疗平台，为临床转化和治疗增强提供了机制性见解。

展开英文摘要原文

Immune checkpoint inhibitors (ICIs) have revolutionized lung cancer treatment, yet resistance remains a challenge. Co-inhibition of PD-1/PD-L1 and TGF-β shows promise but faces limited efficacy and systemic toxicity.

We developed gelatinase-responsive nanoparticles (GPNPs) delivering anti-PD-1 antibody (αPD-1) and TGF-β receptor I inhibitor galunisertib (Gal). GPNPs effectively inhibit tumor progression without observed side effects. Immune profiling by cytometry assay reveals robust recruitment of both activated and exhausted tumor-infiltrating lymphocytes (TILs) and macrophages.

Transcriptomic analysis indicates extracellular matrix modulation, supported by reduced collagen deposition and αSMA expression. Fate mapping demonstrates attenuation of Pdgfrα + fibroblast transition to αSMA myofibroblasts, potentially reversing "immune-exclusive" status.

This study validates GPNPs as a promising lung cancer immunotherapy platform, offering mechanistic insights for clinical translation and therapeutic enhancement.

论文信息

作者
Yen YT、Zhang Z、Chen A、Qiu Y、Liu Q、Wang Q、Li C、Wang C
第一作者单位
The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.China
通讯作者单位
The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China. rutianli@nju.edu.cn.China
期刊
Journal of nanobiotechnology2025 Feb 19
原文标识
PubMed 39972327　·　DOI 10.1186/s12951-025-03129-z

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