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靶向PD-1和TGF-β通路的酶响应性纳米载体可逆转免疫治疗耐药性并引发强大的治疗效果。

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

作者信息

Yen Ying-Tzu, Zhang Zhifan, Chen Anni, Qiu Yuling, Liu Qin, Wang Qin, Li Chunhua, Wang Chun, Qian Xiaoping, Shao Jie, Meng Fanyan, Yu Lixia, Liu Baorui, Li Rutian

机构信息

The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, 210008, China.

The Comprehensive Cancer Center of Nanjing Drum Tower Hospital, Clinical College of Nanjing Drum Tower Hospital, Nanjing University of Chinese Medicine, Nanjing, 210008, China.

出版信息

J Nanobiotechnology. 2025 Feb 19;23(1):124. doi: 10.1186/s12951-025-03129-z.

Abstract

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.

摘要

免疫检查点抑制剂(ICIs)彻底改变了肺癌治疗方式,但耐药性仍是一个挑战。同时抑制PD-1/PD-L1和TGF-β显示出前景,但面临疗效有限和全身毒性的问题。我们开发了可递送抗PD-1抗体(αPD-1)和TGF-β受体I抑制剂加芦米司特(Gal)的明胶酶响应纳米颗粒(GPNPs)。GPNPs有效抑制肿瘤进展,且未观察到副作用。通过细胞计数法进行的免疫分析显示,活化和耗竭的肿瘤浸润淋巴细胞(TILs)以及巨噬细胞大量募集。转录组分析表明细胞外基质发生了改变,这得到了胶原沉积减少和αSMA表达降低的支持。命运图谱显示Pdgfrα成纤维细胞向αSMA肌成纤维细胞的转变减弱,可能逆转“免疫排他性”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的有效性,为临床转化和治疗增强提供了机制性见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/1e94/11841268/6d566d7b3901/12951_2025_3129_Fig1_HTML.jpg

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