大连理工大学樊江莉团队近日实现了吡唑啉酮修饰光敏剂用于精确细胞膜破裂以增强癌症免疫治疗。这一研究成果于2025年5月15日发表在《美国化学会志》上。

免疫疗法的发展旨在彻底根除肿瘤。然而，一些关键的挑战阻碍了传统光疗介导的免疫反应的有效性，包括免疫原性不足和免疫抑制肿瘤微环境的存在。非程序性细胞死亡作为一种高度免疫原性的途径，为增强免疫应答提供了一种有前景的策略。

研究组通过将硒取代的苯并吩噻嗪光敏剂与吡唑啉酮基团偶联，开发了一种膜锚定光动力免疫治疗剂PNBSe，通过吡唑啉酮与蛋白质的相互作用实现膜靶向。在光照射下，PNBSe诱导快速和强烈的细胞坏死，表现为明显的细胞膜破裂、细胞器肿胀和内容物渗漏。进一步的研究表明，PNBSe激活炎症信号通路，诱导免疫原性细胞死亡，重塑免疫抑制性肿瘤微环境，最终促进体内全身抗肿瘤免疫应答。这种膜锚定小分子为促进癌症光动力免疫治疗提供了新的视角。

附：英文原文

Title: Pyrazolone-Modified Photosensitizers for Precise Cell Membrane Rupture to Enhance Cancer Immunotherapy

Author: Yingchao Chen, Tao Xiong, Mingrui Gu, Mingle Li, Xiaoqiang Chen, Lei Wang, Jiangli Fan, Xiaojun Peng

Issue&Volume: May 15, 2025

Abstract: The advancement of immunotherapy aims to achieve complete tumor eradication. However, several critical challenges hinder the efficacy of conventional phototherapy-mediated immune responses, including insufficient immunogenicity and the presence of an immunosuppressive tumor microenvironment. Nonprogrammed cell death, as a highly immunogenic pathway, offers a promising strategy to enhance immune responses. Herein, a membrane-anchored photodynamic immunotherapy agent, PNBSe, was developed by conjugating a selenium-substituted benzophenothiazine photosensitizer with a pyrazolone group, enabling membrane targeting via pyrazolone–protein interactions. Upon light irradiation, PNBSe induced rapid and intense cell necrosis characterized by significant cell membrane rupture, organelle swelling, and content leakage. Further investigations demonstrated that PNBSe activated inflammatory signaling pathways, induced immunogenic cell death, and reshaped the immunosuppressive tumor microenvironment, ultimately promoting systemic antitumor immune responses in vivo. This membrane-anchored small molecule provides a novel perspective for promoting cancer photodynamic immunotherapy.

DOI: 10.1021/jacs.5c02764

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c02764