Theranostics · 2026
A clinically translatable, irreversibly attenuated Salmonella strain as a next-generation adjuvant for checkpoint immunotherapy.
СтатьяНазвание и аннотация: Перевод пока не подготовлен
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Nguyen Dinh-Huy, You Sung-Hwan, Van Nguyen Khuynh, Nguyen Phuong Thi-Minh, Ngo Hien Thi-Thu, Tran Khang Vuong, Tran Thanh Quang, Song Miryoung, Hong Yeongjin, Min Jung-Joon
Аннотация
RATIONALE: The immunosuppressive tumor microenvironment (TME) remains a major barrier to the efficacy of immune checkpoint blockade (ICB) therapy, underscoring the need for strategies that can safely reprogram the TME to enhance cancer immunity.
METHODS: Here, we developed CNC018, a clinically translatable Salmonella typhimurium (SL) strain designed to reprogram the TME and potentiate responses to ICB. CNC018 was constructed using the ppGpp-defective Salmonella strain (SL∆ppGpp, ΔrelA/ΔspoT deletion) as a genetic backbone, with the additional deletion of Salmonella pathogenicity island 1 and 2 (SPI-1 and SPI-2), which are essential for host cell invasion and intracellular survival. These modifications effectively eliminated the risk of virulence restoration.
RESULTS: CNC018 exhibited markedly reduced intracellular invasiveness, was rapidly cleared from non-tumor tissues, and displayed a 2.2-fold higher median lethal dose compared with SL∆ppGpp. Preferentially accumulating within tumors, CNC018 inhibited both primary and metastatic tumor growth in murine, human, and patient-derived xenograft models. CNC018 also induced tumor-derived damage-associated molecular patterns, which activated DCs and tumor-specific CD8⁺ T cells through the TLR4-NF-κB, JAK-STAT-IRF1, and NLRP3 inflammasome signaling pathways. Flow cytometry and single-cell RNA-sequencing revealed that CNC018 dramatically modulated immune checkpoint expression in the TME and tumor-draining lymph nodes, upregulating PD-L1 on tumor cells and dendritic cells and CTLA-4 on regulatory T cells, while downregulating PD-1 on effector T cells. This checkpoint modulation sensitized tumors to anti-PD-L1 and anti-CTLA-4 therapy, achieving synergistic tumor eradication and inducing durable, tumor-specific T-cell memory against tumor rechallenge.
CONCLUSIONS: CNC018 represents a promising next-generation bacterial adjuvant with strong translational potential to safely enhance ICB efficacy in clinical cancer therapy.
METHODS: Here, we developed CNC018, a clinically translatable Salmonella typhimurium (SL) strain designed to reprogram the TME and potentiate responses to ICB. CNC018 was constructed using the ppGpp-defective Salmonella strain (SL∆ppGpp, ΔrelA/ΔspoT deletion) as a genetic backbone, with the additional deletion of Salmonella pathogenicity island 1 and 2 (SPI-1 and SPI-2), which are essential for host cell invasion and intracellular survival. These modifications effectively eliminated the risk of virulence restoration.
RESULTS: CNC018 exhibited markedly reduced intracellular invasiveness, was rapidly cleared from non-tumor tissues, and displayed a 2.2-fold higher median lethal dose compared with SL∆ppGpp. Preferentially accumulating within tumors, CNC018 inhibited both primary and metastatic tumor growth in murine, human, and patient-derived xenograft models. CNC018 also induced tumor-derived damage-associated molecular patterns, which activated DCs and tumor-specific CD8⁺ T cells through the TLR4-NF-κB, JAK-STAT-IRF1, and NLRP3 inflammasome signaling pathways. Flow cytometry and single-cell RNA-sequencing revealed that CNC018 dramatically modulated immune checkpoint expression in the TME and tumor-draining lymph nodes, upregulating PD-L1 on tumor cells and dendritic cells and CTLA-4 on regulatory T cells, while downregulating PD-1 on effector T cells. This checkpoint modulation sensitized tumors to anti-PD-L1 and anti-CTLA-4 therapy, achieving synergistic tumor eradication and inducing durable, tumor-specific T-cell memory against tumor rechallenge.
CONCLUSIONS: CNC018 represents a promising next-generation bacterial adjuvant with strong translational potential to safely enhance ICB efficacy in clinical cancer therapy.