南开大学丁丹团队报道了癌细胞溶酶体中酶指令集合的靶向富集使免疫冷肿瘤变热。相关研究成果于2021年10月13日发表在国际顶尖学术期刊《德国应用化学》。

溶酶体膜透化（LMP）引起的溶酶体相关细胞死亡近年来受到越来越多的关注。然而，几乎没有研究表明，目前可用的LMP诱导剂可以引起免疫原性细胞死亡（ICD）或将免疫性冷肿瘤转化为热肿瘤。

该文中，研究人员报道了一种名为TPE-Py-pYK（TPP）Py的LMP诱导剂，可以对碱性磷酸酶（ALP）产生反应，导致纳米组装体的形成，并伴随荧光和单线态氧的开启。TPE-Py-pYK（TPP）Py倾向于在ALP过度表达的癌细胞溶酶体中积累，并诱导LMP和溶酶体膜破裂，从而大量诱发ICD。该LMP诱导的ICD有效地将免疫性冷肿瘤转化为热肿瘤，大量的CD8+和CD4+T细胞浸润到冷肿瘤中就证明了这一点。将癌细胞溶酶体中的ALP催化纳米组装体暴露于光下进一步强化LMP、ICD和肿瘤从冷到热的转化过程。

该项工作在溶酶体相关细胞死亡和癌症免疫治疗之间建立了一座新的桥梁。

附：英文原文

Title: Targeted Enrichment of Enzyme-Instructed Assemblies in Cancer Cell Lysosomes Turns Immunologically Cold Tumors Hot

Author: Shenglu Ji, Jun Li, Xingchen Duan, Jingtian Zhang, Yufan Zhang, Mengqing Song, Songge Li, Hongli Chen, Dan Ding

Issue&Volume: 2021-10-13

Abstract: Lysosome-relevant cell death induced by lysosomal membrane permeabilization (LMP) has recently attracted increasing attention. However, nearly no studies show that currently available LMP inducers can evoke immunogenic cell death (ICD) or convert immunologically cold tumors to hot. Herein, we report a LMP inducer named TPE-Py-pYK(TPP)pY, which can respond to alkaline phosphatase (ALP), leading to formation of nanoassembies along with fluorescence and singlet oxygen turn-on. TPE-Py-pYK(TPP)pY tends to accumulate in ALP-overexpressed cancer cell lysosomes as well as induce LMP and rupture of lysosomal membranes to massively evoke ICD. Such LMP-induced ICD effectively converts immunologically cold tumors to hot as evidenced by abundant CD8+ and CD4+ T cells infiltration into the cold tumors. Exposure of ALP-catalyzed nanoassemblies in cancer cell lysosomes to light further intensifies the processes of LMP, ICD and cold-to-hot tumor conversion. This work thus builds a new bridge between lysosome-relevant cell death and cancer immunotherapy.

DOI: 10.1002/anie.202110512

Source: https://onlinelibrary.wiley.com/doi/10.1002/anie.202110512