What is it about?
Elucidating the mechanisms underlying antitumor immunity is critical for improving the efficacy of cancer immunotherapy. In this study, we reveal how a molecule called WFDC21P boosts the immune response to fight triple-negative breast cancer (TNBC). This long non-coding RNA helps activate the RIG-I immune pathway—a key alarm system against viruses and tumors. WFDC21P binds to the protein G3BP1, promoting the formation of liquid-like droplets (phase separation) that rapidly trigger RIG-I. This leads to upregulated expression of IFNs, enhancing CD8+ T cell infiltration and killing of cancer cells. Importantly, low WFDC21P levels in patients correlate with poor outcomes. Restoring it not only suppresses tumor growth but also improves response to immunotherapy, offering a promising new combination strategy for TNBC.
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Why is it important?
We elucidate an immune evasion mechanism driven by WFDC21P downregulation—a common event in triple-negative breast cancer and a spectrum of cancer. As a key positive regulator of the RIG-I pathway, WFDC21P is required for the formation of functional G3BP1–RIG-I–dsRNA liquid-like condensates, thereby ensuring efficient dsRNA recognition and robust activation of interferon signaling. Together, our findings establish WFDC21P as a molecular gatekeeper of tumor-intrinsic RNA sensing and highlight the potential of restoring WFDC21P in combination with immune checkpoint inhibitors for cancer treatments.
Perspectives
Activation of RNA-sensing pathways is increasingly recognized for its role in anti-tumor immunity. Our study identifies a lncRNA called WFDC21P as an essential orchestrator of G3BP1–RIG-I–dsRNA condensates, which are critical for activating the RNA sensor RIG-I. Cancer cells suppress WFDC21P to evade this immune response. Restoring WFDC21P expression to reboot the RNA-sensing pathway therefore holds promise for enhancing the efficacy of cancer immunotherapy.
Man-Li Luo
Sun Yat-Sen University
Read the Original
This page is a summary of: WFDC21P is essential for G3BP1-mediated RIG-I activation and antitumor immunity in triple-negative breast cancer, Proceedings of the National Academy of Sciences, March 2026, Proceedings of the National Academy of Sciences,
DOI: 10.1073/pnas.2532576123.
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