NLRP3 activation promotes cGAS/STING signaling and antitumor immunity by colorectal cancer cells
Abstract Introduction Colorectal cancer (CRC) is a highly prevalent and deadly disease that is largely refractory to immunotherapy. The only CRC subset that responds to these therapies is characterized by prevalent microsatellite instability (MSI), extensive CD8+ T cell infiltration and high expres...
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| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
| Published: |
Springer
2025-06-01
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| Series: | Cancer Immunology, Immunotherapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s00262-025-04088-y |
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| Summary: | Abstract Introduction Colorectal cancer (CRC) is a highly prevalent and deadly disease that is largely refractory to immunotherapy. The only CRC subset that responds to these therapies is characterized by prevalent microsatellite instability (MSI), extensive CD8+ T cell infiltration and high expression of innate immune signaling pathways. Endogenous activation of the cGAS/STING pathway is essential for this CD8+ T cell antitumor response in MSI CRCs, suggesting that activating it in other CRCs could boost immunotherapy response rates. In contrast, activation of the NLRP3 inflammasome is typically associated with tumor-promoting inflammation although this has primarily been studied in immune cells. Methods We used a mixture of flow cytometry, activation assays, in vivo orthotopic models and patient-derived organoids to investigate the effect of NLRP3 activation in CRC cells on cGAS/STING-mediated antitumor immunity. Results Our results show that activation of the NLRP3 inflammasome specifically in CRC cells boosts cGAS/STING signaling in both MSI and non-MSI CRCs and that dual stimulation increases CD8+ T cell-mediated antitumor immunity. The ability of NLRP3 to enhance cGAS/STING signaling was specific and did not occur with activation of other innate immune pathways such as AIM2 or TLRs. Enhancement of cGAS/STING signaling by NLRP3 proceeded via a positive feedback loop that was inflammasome-independent and required early crosstalk between the signaling mediators and regulation of their gene expression. Conclusions Activation of NLRP3 specifically in CRC cells could be a promising strategy to boost antitumor immunity in otherwise immunotherapy resistant CRCs. |
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| ISSN: | 1432-0851 |