NOD2 restrains probiotic-mediated TLR2-dependent antitumor immunity
- 1Scripps Research
Abstract
The gut microbiota influences cancer immunotherapy, but how interactions among host microbial sensors determine the activity of individual bacteria remains unclear. Here, we show that NOD2 restrains TLR2-dependent antitumor immunity induced by Lactiplantibacillus plantarum. Oral administration of live or heat-killed L. plantarum enhanced immune checkpoint blockade efficacy in mouse tumor models. This activity required host TLR2 signaling and was diminished by disruption of bacterial lipoprotein. In contrast, NOD2 deficiency enhanced tumor control, intratumoral interferon-associated programs, and T cell activation. NOD2 deficiency also amplified chemokine and interferon-associated responses to L. plantarum and the synthetic TLR2 agonist Pam3CSK4 in myeloid cells. Genetic loss or pharmacological inhibition of NOD2 improved Pam3CSK4-mediated tumor control in combination with checkpoint blockade. These findings identify NOD2 as a functional checkpoint on TLR2-driven antitumor immunity and demonstrate that interactions between host microbial-sensing pathways shape the therapeutic activity of commensal bacteria and innate immune agonists.
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BibTeX
@misc{zhang2026nod2,
title = {{NOD2 restrains probiotic-mediated TLR2-dependent antitumor immunity}},
author = {X. Zhang and N. Dudkina and K. T. Fam and S. Dikiy and A. M. Turner and A. Vu-Nguyen and B. A. Nguyen and T. Dai and H. C. Hang},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.08.757712},
url = {https://www.biorxiv.org/content/10.64898/2026.10.08.757712v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - NOD2 restrains probiotic-mediated TLR2-dependent antitumor immunity
AU - X. Zhang
AU - N. Dudkina
AU - K. T. Fam
AU - S. Dikiy
AU - A. M. Turner
AU - A. Vu-Nguyen
AU - B. A. Nguyen
AU - T. Dai
AU - H. C. Hang
PY - 2026
DA - 2026/10/08
PB - bioRxiv
DO - 10.64898/2026.10.08.757712
UR - https://www.biorxiv.org/content/10.64898/2026.10.08.757712v1
AB - The gut microbiota influences cancer immunotherapy, but how interactions among host microbial sensors determine the activity of individual bacteria remains unclear. Here, we show that NOD2 restrains TLR2-dependent antitumor immunity induced by Lactiplantibacillus plantarum. Oral administration of live or heat-killed L. plantarum enhanced immune checkpoint blockade efficacy in mouse tumor models. This activity required host TLR2 signaling and was diminished by disruption of bacterial lipoprotein. In contrast, NOD2 deficiency enhanced tumor control, intratumoral interferon-associated programs, and T cell activation. NOD2 deficiency also amplified chemokine and interferon-associated responses to L. plantarum and the synthetic TLR2 agonist Pam3CSK4 in myeloid cells. Genetic loss or pharmacological inhibition of NOD2 improved Pam3CSK4-mediated tumor control in combination with checkpoint blockade. These findings identify NOD2 as a functional checkpoint on TLR2-driven antitumor immunity and demonstrate that interactions between host microbial-sensing pathways shape the therapeutic activity of commensal bacteria and innate immune agonists.
ER -