<br>将肿瘤内细菌转化为免疫增强剂以逆转冷肿瘤，增强三阴性乳腺癌的免疫化学动力学治疗,Journal of the American Chemical Society

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将肿瘤内细菌转化为免疫增强剂以逆转冷肿瘤，增强三阴性乳腺癌的免疫化学动力学治疗
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2023-11-21 , DOI: 10.1021/jacs.3c09472
Xuemeng Liu _{1,

2} , Mengyu Sun _{1,

2} , Fang Pu _{1,

2} , Jinsong Ren _{1,

2} , Xiaogang Qu _{1,

2}

Affiliation

由于免疫学上的“冷”微环境，三阴性乳腺癌（TNBC）的免疫疗法的治疗效果并不令人满意。具核梭杆菌（ F. nucleatum ）被发现定植于三阴性乳腺肿瘤中，并负责免疫抑制肿瘤微环境和肿瘤转移。在此，我们构建了一种细菌源性外膜囊泡（OMV）包被的纳米平台，可精确靶向肿瘤组织，对具核梭菌和癌细胞进行双重杀伤，从而将肿瘤内细菌转化为TNBC免疫治疗中的免疫增强剂。所制备的纳米粒子通过类芬顿反应有效诱导免疫原性细胞死亡，从而增强免疫原性。同时，瘤内具核梭杆菌被甲硝唑杀死，导致病原体相关分子模式（PAMP）的释放。 PAMPs 与 OMVs 合作进一步促进树突状细胞的成熟和随后的 T 细胞浸润。由此，“一石二鸟”的策略温暖了寒冷的肿瘤环境，最大限度地提高了抗肿瘤免疫反应，实现了TNBC的高效治疗和转移预防。总体而言，这种基于肿瘤和正常组织的微生态差异以及微生物组诱导的冷肿瘤逆转的策略为 TNBC 的精确有效的免疫治疗提供了新的见解。

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Transforming Intratumor Bacteria into Immunopotentiators to Reverse Cold Tumors for Enhanced Immuno-chemodynamic Therapy of Triple-Negative Breast Cancer

Immunotherapy of triple-negative breast cancer (TNBC) has an unsatisfactory therapeutic outcome due to an immunologically “cold” microenvironment. Fusobacterium nucleatum (F. nucleatum) was found to be colonized in triple-negative breast tumors and was responsible for the immunosuppressive tumor microenvironment and tumor metastasis. Herein, we constructed a bacteria-derived outer membrane vesicle (OMV)-coated nanoplatform that precisely targeted tumor tissues for dual killing of F. nucleatum and cancer cells, thus transforming intratumor bacteria into immunopotentiators in immunotherapy of TNBC. The as-prepared nanoparticles efficiently induced immunogenic cell death through a Fenton-like reaction, resulting in enhanced immunogenicity. Meanwhile, intratumoral F. nucleatum was killed by metronidazole, resulting in the release of pathogen-associated molecular patterns (PAMPs). PAMPs cooperated with OMVs further facilitated the maturation of dendritic cells and subsequent T-cell infiltration. As a result, the “kill two birds with one stone” strategy warmed up the cold tumor environment, maximized the antitumor immune response, and achieved efficient therapy of TNBC as well as metastasis prevention. Overall, this strategy based on a microecology distinction in tumor and normal tissue as well as microbiome-induced reversal of cold tumors provides new insight into the precise and efficient immune therapy of TNBC.

更新日期：2023-11-21

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