A novel AIE photosensitizer for combination photodynamic immunotherapy via autophagy activation and tumor microenvironment modulation

IF 5.9 2区医学 Q1 CHEMISTRY, MEDICINAL

European Journal of Medicinal Chemistry Pub Date : 2025-09-16 DOI:10.1016/j.ejmech.2025.118155

De-rong Wang, Xian-li Ma, Jing-jing Li, Cheng-kun Li, Qian Li, Fang-yao Li

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引用次数: 0

Abstract

The limited efficacy of cancer immunotherapy is often attributed to insufficient tumor immunogenicity and the presence of an immunosuppressive tumor microenvironment (ITM). To address these challenges, we developed a novel photosensitizer (PS), TTVBO-1MT, by conjugating the indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor 1-methyl-d-tryptophan (1-MT) to the aggregation-induced emission (AIE) PS TTVBO via a glutathione (GSH)-responsive linker. Comprehensive in vitro and in vivo evaluations using a model of triple-negative breast cancer revealed that TTVBO-1MT exhibited potent antitumor activity. Mechanistic studies demonstrated that TTVBO-1MT mediated photoimmunotherapy through dual mechanisms involving autophagy induction and IDO1 inhibition. The photodynamic effect led to the induction of immunogenic cell death (ICD), while the glutathione-responsive release of 1-MT suppressed IDO1 activity, decreased Foxp3 expression, and reduced regulatory T cell (Treg) populations, thereby mitigating immunosuppression. This combined effect promoted T-cell infiltration and triggered a systemic antitumor immune response. Overall, the results suggest that TTVBO-1MT enables autophagy-assisted immuno-photodynamic modulation of the tumor microenvironment (TME), offering significant therapeutic potential.

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一种通过自噬激活和肿瘤微环境调节联合光动力免疫治疗的新型AIE光敏剂

癌症免疫治疗的有限疗效通常归因于肿瘤免疫原性不足和免疫抑制肿瘤微环境（ITM）的存在。为了解决这些挑战，我们开发了一种新型光敏剂TTVBO- 1mt，通过谷胱甘肽（GSH）响应连接将吲哚胺2,3-双加氧酶1 （IDO1）抑制剂1-甲基-d -色氨酸（1- mt）偶联到聚集诱导发射（AIE） PS TTVBO上。利用三阴性乳腺癌模型进行的综合体外和体内评价显示，TTVBO-1MT具有强大的抗肿瘤活性。机制研究表明TTVBO-1MT通过诱导自噬和抑制IDO1的双重机制介导光免疫治疗。光动力效应导致免疫原性细胞死亡（ICD），而谷胱甘肽响应性释放1-MT抑制IDO1活性，降低Foxp3表达，减少调节性T细胞（Treg）数量，从而减轻免疫抑制。这种综合作用促进t细胞浸润并引发全身抗肿瘤免疫反应。总的来说，结果表明TTVBO-1MT能够自噬辅助免疫光动力调节肿瘤微环境（TME），具有显著的治疗潜力。

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来源期刊

European Journal of Medicinal Chemistry 化学-医药化学

CiteScore

11.70

自引率

9.00%

发文量

863

审稿时长

29 days

期刊介绍： The European Journal of Medicinal Chemistry is a global journal that publishes studies on all aspects of medicinal chemistry. It provides a medium for publication of original papers and also welcomes critical review papers. A typical paper would report on the organic synthesis, characterization and pharmacological evaluation of compounds. Other topics of interest are drug design, QSAR, molecular modeling, drug-receptor interactions, molecular aspects of drug metabolism, prodrug synthesis and drug targeting. The journal expects manuscripts to present the rational for a study, provide insight into the design of compounds or understanding of mechanism, or clarify the targets.