Stem Cell–Neutrophil Crosstalk Modulates Immunotherapy Response

While immune checkpoint blockade has become a cornerstone of cancer therapy, treatment responses can be transient, and the disease often relapses. In this study, Guo, Luan, and colleagues explored the effects of immunotherapy on tumor-associated neutrophils (TAN) in mouse models of squamous cell carcinoma (SCC). In untreated autochthonous SCC tumors, distinct subsets of TANs displayed both unique and common immune-suppressive features. Anti–PD-L1 + CD40 agonist treatment cleared tumors and led to the expansion of mature TAN subsets displaying upregulation of interferon (IFN)-stimulated genes. In an engrafted SCC model, pre-treatment neutrophil depletion enhanced the antitumor activity of infiltrating T cells, while post-treatment neutrophil depletion reduced tumor control by T cells. Immunotherapy increased the expression of LY6E and MHC and decreased Siglec-F levels in TANs. Lineage tracing experiments revealed that TANs located within the tumor microenvironment (TME) acquired antitumor activities after treatment, suggesting that immunotherapy reprogrammed TAN function. Additionally, blocking IFN signaling prevented TAN phenotype switching and abolished T-cell antitumor activity, reducing the efficacy of immunotherapy. Spatial transcriptomic analysis demonstrated that stromal TANs showed significant upregulation of IFN signaling and other antitumor activities, while TANs located at the tumor–stroma interface did not. Tumor-initiating stem cells (tSC), which accumulate at the tumor–stroma interface, exhibited SOX2 upregulation, and only SOX2high tumor regions were associated with immunosuppressive TANs following treatment. Sox2 deletion in the basal epithelium led to TAN antitumor reprogramming, enhanced interactions between TANs and T cells in both the stroma and tumor mass, and prevented post-treatment relapse. SOX2 was found to directly bind the promoter of Fads1 and induce its expression, leading to arachidonic acid (AA) production and metabolism into prostaglandin E2 (PGE2). Finally, blocking PGE2 production using COX-2 inhibitors activated IFN signaling in TANs and reduced relapse following immunotherapy. Altogether, this study shows that tSCs can block immunotherapy-induced TAN reprogramming and form a protective niche that facilitates disease relapse.Guo W, Luan J, Huang X, Leon D, Gang S, Nicholson B, et al. Tumor-initiating stem cells fine-tune the plasticity of neutrophils to sculpt a protective niche. Cancer Cell 2026;44:94–111.Note: Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at https://aacrjournals.org/cdnews.