2. Academic Validation
  3. Microbial-derived immunostimulatory small molecule augments anti-PD-1 therapy in lung cancer

Microbial-derived immunostimulatory small molecule augments anti-PD-1 therapy in lung cancer

  • Cell Rep Med. 2025 Dec 19:102519. doi: 10.1016/j.xcrm.2025.102519.
Rachel C Newsome 1,  Huijia Liu 1,  Bright Agbodzi 2,  Raad Z Gharaibeh 3,  Liang Zhou 4,  Christian Jobin 5
Affiliations

Affiliations

  • 1 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA.
  • 2 UF Genetics Institute, University of Florida, Gainesville, FL, USA.
  • 3 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA.
  • 4 Department of Infectious Diseases and Immunology, University of Florida College of Medicine, Gainesville, FL, USA.
  • 5 Department of Medicine, University of Florida College of Medicine, Gainesville, FL, USA; Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA; Department of Infectious Diseases and Immunology, University of Florida College of Medicine, Gainesville, FL, USA. Electronic address: [email protected].
PMID: 41421351 DOI: 10.1016/j.xcrm.2025.102519
Abstract

We previously showed that enrichment of the Bacteroides genus is associated with improved anti-PD-1-mediated tumor therapy. Here, we isolate 183 Bacteroides isolates from the feces of humanized anti-PD-1 responder mice. Supernatants from 6 of 183 isolates stimulate IFNγ production from primary CD8+ T cells. These six isolates (6-consort) enhance anti-PD-1-induced anti-tumor efficacy in syngeneic and orthotopic lung Cancer models compared to non-responder feces-colonized mice, an effect dependent on the production of IFNγ. Bioassay-guided fractionation and comparative metabolomics lead to the discovery of an active N-acyl amide (cis-Bac429) produced by Bacteroides. cis-Bac429 stimulates IFNγ production by CD8+ T cells but not synthetic saturated Bac429 (sat-Bac429), indicating structural specificity. Intratumorally administered cis-Bac429, but not sat-Bac429, significantly decreases subcutaneous lung and colon tumor growth in combination with anti-PD-1 therapy and drives IFNγ+ CD8+ T cell tumor infiltration. These findings pave the way for development of Bacteroides-type N-acyl-amides as Adjuvant treatments for anti-PD-1-refractory NSCLC.

Keywords

immune checkpoint inhibition; immunotherapy; microbiome; non-small cell lung cancer.

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