中国科学院上海药物研究所于海军团队探索了超声活化免疫凝胶治疗乳腺癌免疫代谢紊乱的工程研究。相关论文于2025年6月23日发表在《美国化学会志》上。

声动力疗法（SDT）是一种很有前途的实体瘤局部免疫治疗方法，但其临床转化受到治疗应激诱导的适应性免疫抵抗的限制。

研究组证明SDT最初引发抗肿瘤免疫应答，随后通过干扰素-γ (IFN-γ)/吲哚胺-2,3-双加氧酶-1 （IDO-1）轴诱导免疫代谢失调，促进调节性T细胞（Treg）扩增。为了抵消这种负调节机制，研究组通过超声不稳定的尿素键将声敏剂亚甲基蓝（MB）与IDO-1抑制剂1-甲基色氨酸（MT）偶联，开发了一种声激活前药（MB - MT）。

MB-MT进一步掺入热敏水凝胶中，产生超声反应性免疫凝胶，在局部抑制IDO-1介导的免疫抑制的同时，实现时空受限的SDT。在三阴性乳腺癌（TNBC）的多协同多主题模型中，免疫凝胶联合SDT治疗可显著使免疫抑制的肿瘤微环境正常化，从而抑制原发和转移性肿瘤的生长，并预防术后复发。这项工作提出了一个实用的策略，局部免疫治疗TNBC的时空限制的正常化免疫代谢紊乱。

附：英文原文

Title: Engineering of Sono-Activatable Immunogels for Immunometabolism Disorder Normalization Therapy of Breast Cancer

Author: Yu Guo, Jiaxing Pan, Junjue Wang, Huijuan Zhang, Wenfang Yang, Fangmin Chen, Bowen Yin, Xiran Cai, Wei Tao, Twan Lammers, Yi Lai, Haijun Yu, Xiuli Hu, Zhiai Xu

Issue&Volume: June 23, 2025

Abstract: Sonodynamic therapy (SDT) represents a promising approach for localized immunotherapy of solid tumors, yet its clinical translation is limited by therapy stress-induced adaptive immune resistance. Here, we demonstrate that SDT initially elicits antitumor immune response while consequently induces immunometabolic dysregulation via the interferon-gamma (IFN-γ)/indoleamine-2,3-dioxygenase-1 (IDO-1) axis to promote regulatory T cell (Treg) expansion. To counteract this negative regulation mechanism, we develop a sono-activatable prodrug (MB–MT) by conjugating the sonosensitizer methylene blue (MB) with the IDO-1 inhibitor 1-methyltryptophan (MT) via an ultrasound-labile urea bond. MB–MT is  further incorporated into a thermosensitive hydrogel to yield an ultrasound-responsive immunogel that enables spatiotemporally confined SDT while locally suppressing IDO-1-mediated immune suppression. The combination of the immunogel with SDT treatment markedly normalizes the immunosuppressive tumor microenvironment to inhibit primary and metastatic tumor growth, and prevent postoperative recurrence in multiple synergistic mouse models of triple negative breast cancer (TNBC). This work presents a practical strategy for localized immunotherapy of TNBC by spatiotemporally confined normalization of immunometabolism disorder.

DOI: 10.1021/jacs.5c00124

Source: https://pubs.acs.org/doi/abs/10.1021/jacs.5c00124