Profilin-1 Deficiency Activates Immune Response Against Breast Cancer in Preclinical Study
Researchers found that deleting the gene Profilin-1 (Pfn1) in breast cancer cells causes genomic instability that activates the cGAS-STING immune signaling pathway, recruiting CD8+ T cells to destroy tumors. The study used an inducible CRISPR/Cas9 knockout system in both cell lines and immunocompetent mouse models to demonstrate the effect. The findings suggest that targeting Pfn1-driven pathways could be a new strategy to enhance immunotherapy outcomes in breast cancer.
A preprint study on bioRxiv reports that loss of Profilin-1 (Pfn1), an actin-binding protein, in breast cancer cells sets off a chain of events leading to robust immune-mediated tumor regression. Using inducible CRISPR/Cas9 knockout technology, researchers showed that Pfn1 depletion causes genomic instability — including polyploidy, micronuclei formation, and DNA damage — along with defects in both homologous recombination and non-homologous end-joining DNA repair pathways. These disruptions lead to nuclear envelope abnormalities and the leakage of DNA into the cytoplasm, which activates the cGAS-STING nucleic acid-sensing pathway and triggers a type I interferon response along with pro-inflammatory chemokine upregulation. In immunocompetent mouse models, tumor-selective Pfn1 loss produced a striking increase in intratumoral CD8+ T cells and strong tumor regression, an effect that was abolished when CD8+ T cells were depleted or when the immune system was compromised. The authors conclude that Pfn1 loss essentially converts breast tumors into immunogenic targets, opening potential avenues for combining Pfn1 pathway inhibition with existing immunotherapies.
What's missing
As a preprint, this study has not yet undergone formal peer review. The research is currently limited to mouse models and cell lines; it is unknown whether Pfn1 targeting produces similar immune activation in human patients or whether it could have off-target effects in normal tissues that also express Pfn1. The study does not address potential resistance mechanisms or how Pfn1 inhibition might be achieved pharmacologically in a clinical setting.
What different sources said
- bioRxivCenter
Profilin-1 Deficiency Activates STING to Drive T Cell-Mediated Anti-Tumor Immunity in Breast Cancer
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