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<p>Reprogramming tumor-associated macrophages (TAMs) from the pro-tumoral M2-like state to the immunostimulatory M1-like phenotype has emerged as a promising strategy for tumor therapy. However, most M2-like TAMs are preferentially located in hypoxic regions of the tumor, which are poorly accessible to many advanced drug delivery systems, posing a significant challenge to effective TAM reprogramming. Here, leveraging the tropism of facultative anaerobic bacteria to localize and propagate in the hypoxic tumor, an optogenetically engineered <i>Escherichia coli</i> Nissle 1917 strain conjugated with murine STING agonist (EcN<sub>flaB</sub>@UPD) was developed for cancer-specific immunotherapy. Upon near-infrared light illumination, the blue and UV emissions from upconversion nanoparticles (UCNPs) simultaneously activate the expression of Toll-like receptor (TLR) agonist, flaB, from EcN<sub>flaB</sub>, and the release of photocaged murine STING agonist, DMXAA, respectively. This spatiotemporally synchronized dual release ensures co-localized STING and TLR5 agonists inside the hypoxic niche, repolarizing TAMs from the M2 to the M1 phenotype via synergistic TLR5-MAPK1-NF-κB and STING-NF-κB signaling. The polarization of TAMs enhances their antigen-presenting capacity and, more importantly, activates the cytotoxic, stem-like and memory CD8<sup>+</sup> T cells responses. This subsequently inhibits tumor growth, relapse, and metastasis in the murine 4T1 tumor model. Collectively, our work introduces the bacteria-based system that uses near-infrared light to dual-release immunotherapeutics for systemic anti-tumor immunity, opening new avenues for precise and effective cancer immunotherapy.</p> Graphical abstract <p></p>

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Photoactivated probiotic micro-reactor synchronizes STING/TLRs agonists to spatiotemporally synergize antitumor immunotherapy

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月2日

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  • Yuzhi Qiu,
  • Yunting Liu,
  • Sihan Chen,
  • Yidi Liu,
  • Xi Yu,
  • Xiangliang Yang,
  • Yan Zhang,
  • Yanhong Zhu

摘要

Reprogramming tumor-associated macrophages (TAMs) from the pro-tumoral M2-like state to the immunostimulatory M1-like phenotype has emerged as a promising strategy for tumor therapy. However, most M2-like TAMs are preferentially located in hypoxic regions of the tumor, which are poorly accessible to many advanced drug delivery systems, posing a significant challenge to effective TAM reprogramming. Here, leveraging the tropism of facultative anaerobic bacteria to localize and propagate in the hypoxic tumor, an optogenetically engineered Escherichia coli Nissle 1917 strain conjugated with murine STING agonist (EcNflaB@UPD) was developed for cancer-specific immunotherapy. Upon near-infrared light illumination, the blue and UV emissions from upconversion nanoparticles (UCNPs) simultaneously activate the expression of Toll-like receptor (TLR) agonist, flaB, from EcNflaB, and the release of photocaged murine STING agonist, DMXAA, respectively. This spatiotemporally synchronized dual release ensures co-localized STING and TLR5 agonists inside the hypoxic niche, repolarizing TAMs from the M2 to the M1 phenotype via synergistic TLR5-MAPK1-NF-κB and STING-NF-κB signaling. The polarization of TAMs enhances their antigen-presenting capacity and, more importantly, activates the cytotoxic, stem-like and memory CD8+ T cells responses. This subsequently inhibits tumor growth, relapse, and metastasis in the murine 4T1 tumor model. Collectively, our work introduces the bacteria-based system that uses near-infrared light to dual-release immunotherapeutics for systemic anti-tumor immunity, opening new avenues for precise and effective cancer immunotherapy.

Graphical abstract