口服血红素加氧酶抑制剂在临床前癌症模型中靶向免疫抑制的血管周围巨噬细胞

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-08-06 DOI:10.1126/scitranslmed.ads3085

Meriem Bahri, Taha Al-Adhami, Emre Demirel, Jit Sarkar, Karen T. Feehan, Joanne E. Anstee, Tik Shing Cheung, Dominika Sosnowska, Chloé A. Woodman, William Macmorland, Dorothy D. Yang, James Rosekilly, Renee Gitsaki-Taylor, Cheryl E. Gillett, Cheryl L. Scudamore, James Spicer, Khondaker Miraz Rahman, James N. Arnold

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引用次数: 0

摘要

表达淋巴管内皮透明质酸受体-1 （LYVE-1）的血管周围肿瘤相关巨噬细胞（pvtam）亚群依赖血红素加氧酶-1 （HO-1）活性维持免疫冷肿瘤微环境，从而抑制化疗的疗效。因此，HO-1抑制代表了一种针对免疫抑制性LYVE-1 + pvtam并改善治疗反应的策略。我们开发并表征了KCL-HO-1i，一种小分子，口服生物可利用的HO-1抑制剂。在化疗耐药的自发性小鼠MMTV-PyMT乳腺癌和皮下MN/MCA1肉瘤模型中，KCL-HO-1i靶向PvTAM功能可增强化疗效果并使肿瘤对治疗增敏。KCL-HO-1i联合化疗促进了以CD8 + T细胞浸润增加为特征的免疫热肿瘤微环境，具有效应功能。这些发现表明KCL-HO-1i是一种无毒的，口服生物可利用的小分子免疫治疗药物，靶向肿瘤pvtam的关键亚群，提供了一种提高癌症化疗疗效的组合策略。

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An oral heme oxygenase inhibitor targets immunosuppressive perivascular macrophages in preclinical models of cancer

A subset of perivascular tumor-associated macrophages (PvTAMs) expressing lymphatic vessel endothelial hyaluronan receptor–1 (LYVE-1) relies on heme oxygenase–1 (HO-1) activity to maintain an immunologically cold tumor microenvironment, which suppresses the efficacy of chemotherapy. Consequently, HO-1 inhibition represents a strategy to target immunosuppressive LYVE-1 + PvTAMs and improve therapeutic responses. We developed and characterized KCL-HO-1i, a small-molecule, orally bioavailable HO-1 inhibitor. In chemotherapy-resistant spontaneous murine MMTV-PyMT breast cancer and subcutaneous MN/MCA1 sarcoma models, targeting the PvTAM function with KCL-HO-1i enhanced chemotherapy effects and sensitized tumors to treatment. KCL-HO-1i combined with chemotherapy promoted an immunologically hot tumor microenvironment characterized by increased infiltration of CD8 + T cells exhibiting effector function. These findings identify KCL-HO-1i as a nontoxic, orally bioavailable small-molecule immunotherapeutic targeting a key subset of protumoral PvTAMs, offering a combinatorial strategy to enhance chemotherapy efficacy in cancer.

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来源期刊

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.