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Introduction <p>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+&#xa0;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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>Activation of NLRP3 specifically in CRC cells could be a promising strategy to boost antitumor immunity in otherwise immunotherapy resistant CRCs.</p>

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NLRP3 activation promotes cGAS/STING signaling and antitumor immunity by colorectal cancer cells

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年6月7日

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  • Courtney Mowat,
  • Daniel Schiller,
  • Kristi Baker

摘要

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.