A Sampling of Highlights from the Literature: Article Recommendations from Our Deputy and Senior Editors

FOXP3 is the master regulator of Treg function (from AtikaAtikawa via Wikimedia Commons).The function of regulatory T cells (Treg)—immunosuppressive cells that inhibit antitumor immune responses—is controlled by FOXP3, which occurs as two major isoforms in humans. After finding that expression of the shorter isoform with exon 2 skipped, FOXP3dE2, in breast cancer correlates with better patient survival, Li and colleagues studied mice bearing the Foxp3dE2 allele. In multiple preclinical models, tumor growth is abrogated in these mice because of enhanced CD8+ T-cell activation. A morpholino oligo that induces FOXP3 exon 2 skipping, enhances antitumor immunity in mice and tumor-infiltrating T cells in autologous patient-derived tumor organoids, highlighting the therapeutic potential of the study.Li Y, …, Lu X. Sci Immunol 2025 August 22;10,eadr9933.Tumor-induced NRF2 promotes bone-marrow myelopoiesis (From MAKY.OREL via Wikimedia Commons).The mechanisms by which tumors promote bone-marrow myelopoiesis, which leads to increased accumulation of immunosuppressive monocyte-derived macrophages (mo-macs) in the tumor microenvironment (TME), are not clear. In a mouse model of non–small cell lung cancer (NSCLC) and patients with the disease, Hegde and colleagues find that tumor mitogen–induced oxidative stress increases activity of the transcription factor NRF2 in bone-marrow myeloid progenitors, promoting myelopoiesis. NRF2 also drives an immunosuppressive phenotype in mo-macs in the TME. Inhibition of NRF2 combined with anti–PD-1 reduces accumulation of immunosuppressive mo-macs in the TME and tumor burden, suggesting a new target for cancer immunotherapy.Hegde S, …, Merad M. Nature 2025 Sept 10;DOI:10.1038/s41586-025-09493-y.Telomere damage drives T-cell dysfunction in cancer (From U.S. Department of Energy Human Genome Program via Wikimedia Commons).To deepen understanding of how oxidative stress drives T-cell dysfunction in the tumor microenvironment, Rivadeneira and colleagues used a chemo-optogenetic tool that generates singlet oxygen in specific T-cell locations. They demonstrate that oxidative stress originating in mitochondria causes DNA damage at telomeres. This telomeric damage results in diminished cytokine production. Neutralizing reactive oxygen species at telomeres rescues T-cell dysfunction, supporting the hypothesis that telomere damage, but not shortening, induces T-cell dysfunction in cancer. Therapeutics that can protect telomeres may improve cellular immunotherapies for cancer.Rivadeneira DB, …, Delgoffe GM. Immunity 2025 Sept 09;58,2524–2540.E5Synthetic receptors to make T cells function better (from Wolverine1721 via Wikipedia).T-cell responsiveness to cytokines is mediated by JAK–STAT signaling induced by cytokine receptor pairing. Zhao and colleagues explored how orthogonal chimeric cytokine receptors can increase the diversity of JAK–STAT pairings to induce functionally improved non-natural T-cell states. Swapping the orthogonal IL2Rβ intracellular domain (ICD) with the ICD of IL4R, IL20R, IL22R, and GCSFR generates orthogonal chimeric receptors able to redirect T cells to naturally occurring and synthetic cell states with therapeutic potential. This orthogonal chimeric receptor–expressing T cell–editing approach may allow for the generation of chimeric antigen receptor (CAR) T cells with enhanced persistence.Zhao Y, …, Garcia KC. Nature 2025 August 13;645,1039–1050.Iron hijacked from macrophages to tumors in breast cancer (From Alchemist-hp via Wikimedia Commons).The mechanisms underlying bone metastasis are incompletely characterized. Han and colleagues observe enrichment of a subset of iron-rich macrophages that express VCAM1, CD163, and CCR3 in the bone metastatic niche. These macrophages are recruited from erythroblastic islands (EBI) where they typically regulate iron homeostasis and erythropoiesis. In the metastatic niche, these macrophages supply iron to tumor cells, which enables the tumor cells to adapt to the hypoxic bone microenvironment by mimicking erythroblasts. The recruitment of the macrophages away from EBIs reduces the iron supply for erythropoiesis and thereby promotes anemia. The data provide insight into the mechanisms driving bone metastasis and the anemia that often accompanies it.Han Y, …, Kang Y. Cell 2025 Sept 03;DOI:10.1016/j.cell.2025.08.013.The immunogenicity of personalized neoantigen-targeting vaccines can be improved (from NCI\Duncan Comprehensive Cancer Center at Baylor College of Medicine via NCI Visuals).The use of personalized neoantigen-targeting vaccines is not yet optimized. To improve antigen availability, enhance T-cell priming, and reduce immunosuppression, Blass and colleagues formulated one such vaccine with poly-ICLC and Montanide and administered it with local anti-CTLA4 and systemic anti–PD-1 in a phase I trial enrolling melanoma patients. Ex vivo T-cell responses to most of the immunizing neoepitopes are detectable in peripheral blood mononuclear cells from all nine fully vaccinated patients. Vaccination changes the circulating and intratumoral T-cell repertoires, with vaccine-specific T cells detectable until the last study time point assessed, a median of 20 weeks after the final vaccination. The data support further evaluation of this vaccine platform.Blass E, …, Ott PA. Cell 2025 Sept 18;188,5125–5141.e27.