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Peer-reviewedCC BY-NC 4.0Journal for Immunotherapy of Cancer

Intratumoral Klebsiella pneumoniae drives metabolic-immune remodeling and immunotherapy resistance in bladder cancer

  • Ruilin Zhuang1,2,3
  • Zhiming Wu1,2,3
  • Runhao Zheng1,2,3
  • Yuelong Chen4
  • Xingliang Tan1,2,3
  • Xinpei Deng1,2,3
  • Chichen Zhang1,2,3
  • Jiamin Zeng1,2,3
  • Yanjun Wang1,2,3
  • Haixia He5
  • Yang Liu6,7,8,9,10
  • Qianghua Zhou1,2,3
1 more authors
  • Kai Yao1,2,3
10 affiliations
  1. 1Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
  2. 2State Key Laboratory of Oncology in Southern China, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
  3. 3Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
  4. 4Department of Urology, First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
  5. 5Department of Radiation Oncology, Sun Yat-Sen Memorial Hospital, Guangzhou, Guangdong, China
  6. 6Guangdong Microbial Culture Collection Center, Guangzhou, China
  7. 7Key Laboratory of Agricultural Microbiomics and Precision Application (MARA), Guangzhou, China
  8. 8Key Laboratory of Agricultural Microbiome (MARA), Guangzhou, China
  9. 9State Key Laboratory of Applied Microbiology Southern China, Guangzhou, China
  10. 10Institute of Microbiology, Guangdong Academy of Sciences, Guangzhou, China
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Abstract

Background: Immune checkpoint blockade has expanded the therapeutic landscape of bladder cancer, yet durable clinical benefit remains limited, and the tissue-level ecological determinants of therapeutic resistance are incompletely understood. Intratumoral microbiota are increasingly recognized as spatially organized components of cancer ecosystems, but whether microbial dysbiosis within bladder cancer tissues functionally shapes antitumor immunity remains unclear.

Methods: We integrated contamination-controlled 2bRAD-M microbiome profiling with fluorescence in situ hybridization, single-cell transcriptomics, metabolomics, clinical annotation, organoids, and mouse models to characterize intratumoral microbial states and investigate their roles in immune remodeling and immunotherapy response.

Results: Bladder tumors harbored compositionally heterogeneous intratumoral microbial states. Enrichment of Klebsiella pneumoniae (K. pneumoniae) was associated with aggressive disease and reduced immunotherapy benefit, with receiver operating characteristic AUCs of 0.77 and 0.72 in the discovery and validation cohorts, respectively. Mechanistically, K. pneumoniae-associated valylphenylalanine (Val-Phe engaged an SLC15A1-linked epithelial response, activated NF-κB/p65 signaling, and induced an immunoregulatory cytokine program that promoted M2-like macrophage polarization, impaired CD8+ T-cell effector function, remodeled the tumor immune microenvironment, and limited anti-PD-1 efficacy. SLC15A1-guided virtual screening identified MK-0557 as a candidate modulator that restrained tumor growth and improved anti-PD-1 response in preclinical models.

Conclusions: These findings identify intratumoral microbial dysbiosis as a functional regulator of metabolic-immune remodeling in bladder cancer and define the K. pneumoniae-associated valylphenylalanine–SLC15A1–NF-κB/p65 axis as a potential therapeutic target for overcoming resistance to immune checkpoint blockade.

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Cite

BibTeXRIS
BibTeX
@article{zhuang2026intratumoral,
  title = {{Intratumoral Klebsiella pneumoniae drives metabolic-immune remodeling and immunotherapy resistance in bladder cancer}},
  author = {Ruilin Zhuang and Zhiming Wu and Runhao Zheng and Yuelong Chen and Xingliang Tan and Xinpei Deng and Chichen Zhang and Jiamin Zeng and Yanjun Wang and Haixia He and Yang Liu and Qianghua Zhou and Kai Yao},
  journal = {Journal for Immunotherapy of Cancer},
  year = {2026},
  month = oct,
  doi = {10.1136/jitc-2026-016574},
  url = {https://doi.org/10.1136/jitc-2026-016574},
  note = {CC BY-NC 4.0},
}
RIS
TY  - JOUR
TI  - Intratumoral Klebsiella pneumoniae drives metabolic-immune remodeling and immunotherapy resistance in bladder cancer
AU  - Ruilin Zhuang
AU  - Zhiming Wu
AU  - Runhao Zheng
AU  - Yuelong Chen
AU  - Xingliang Tan
AU  - Xinpei Deng
AU  - Chichen Zhang
AU  - Jiamin Zeng
AU  - Yanjun Wang
AU  - Haixia He
AU  - Yang Liu
AU  - Qianghua Zhou
AU  - Kai Yao
PY  - 2026
DA  - 2026/10/27
JO  - Journal for Immunotherapy of Cancer
DO  - 10.1136/jitc-2026-016574
UR  - https://doi.org/10.1136/jitc-2026-016574
AB  - Background: Immune checkpoint blockade has expanded the therapeutic landscape of bladder cancer, yet durable clinical benefit remains limited, and the tissue-level ecological determinants of therapeutic resistance are incompletely understood. Intratumoral microbiota are increasingly recognized as spatially organized components of cancer ecosystems, but whether microbial dysbiosis within bladder cancer tissues functionally shapes antitumor immunity remains unclear.  Methods: We integrated contamination-controlled 2bRAD-M microbiome profiling with fluorescence in situ hybridization, single-cell transcriptomics, metabolomics, clinical annotation, organoids, and mouse models to characterize intratumoral microbial states and investigate their roles in immune remodeling and immunotherapy response.  Results: Bladder tumors harbored compositionally heterogeneous intratumoral microbial states. Enrichment of Klebsiella pneumoniae (K. pneumoniae) was associated with aggressive disease and reduced immunotherapy benefit, with receiver operating characteristic AUCs of 0.77 and 0.72 in the discovery and validation cohorts, respectively. Mechanistically, K. pneumoniae-associated valylphenylalanine (Val-Phe engaged an SLC15A1-linked epithelial response, activated NF-κB/p65 signaling, and induced an immunoregulatory cytokine program that promoted M2-like macrophage polarization, impaired CD8+ T-cell effector function, remodeled the tumor immune microenvironment, and limited anti-PD-1 efficacy. SLC15A1-guided virtual screening identified MK-0557 as a candidate modulator that restrained tumor growth and improved anti-PD-1 response in preclinical models.  Conclusions: These findings identify intratumoral microbial dysbiosis as a functional regulator of metabolic-immune remodeling in bladder cancer and define the K. pneumoniae-associated valylphenylalanine–SLC15A1–NF-κB/p65 axis as a potential therapeutic target for overcoming resistance to immune checkpoint blockade.
SN  - 2051-1426
ER  -