This research identifies how SOX2-high tumor-initiating stem cells (tSCs) survive immunotherapy by manipulating the immune environment to create a protective niche. While immunotherapy typically uses interferons to reprogram tumor-associated neutrophils (TANs) into anti-tumor agents, tSCs at the tumor-stroma interface block this transition. The study reveals that these stem cells utilize a SOX2-FADS1 signaling axis to produce arachidonic acid, which converts into prostaglandin E2 (PGE2). This specific pathway suppresses the interferon response in nearby neutrophils, maintaining their immunosuppressive state and preventing T cell attacks. By disrupting this crosstalk—specifically through COX-2 inhibition—researchers were able to restore neutrophil plasticity and improve the efficacy of cancer treatments. Ultimately, the findings suggest that targeting the metabolic dialogue between stem cells and neutrophils can prevent cancer relapse following immunotherapy.

References:

• Guo W, Luan J, Huang X, et al. Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche[J]. Cancer cell, 2025