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

Inhibitory PD-1 signaling fine tunes TCR signaling (from Walter Bodmer via Wikimedia Commons).The continuous generation of stem-like progenitor CD8+ T (TSL) cells in tumor-draining lymph nodes (tdLN) is important for effective immune checkpoint inhibitor (ICI) therapy. Hor and colleagues provide new insight into the factors promoting and maintaining TSL cells through three-dimensional imaging of tdLNs from a preclinical cancer model. Niches rich in type 1 conventional dendritic cells support the expansion of high-affinity TCF-1+PD-1+SLAMF6+ TSL cells. Persistent T cell–receptor signaling drives TSL proliferation and self-renewal rather than terminal effector differentiation because PD-1 inhibitory signaling counteracts antigen-driven signaling. PD-1 blockade reduces TSL-cell numbers, providing new information to help maximize the efficacy of ICI therapy.Hor JL, …, Germain RN. Nature 2025 Nov 26;DOI:10.1038/s41586-025-09440-x.Neuronal activation in the TME remodels tdLNs (from GerryShaw via Wikimedia Commons).Neuro-immune interactions in the tumor microenvironment (TME) influence antitumor immune responses, but whether they impact the immune system systemically is unclear. Using patient samples and multiple mouse models of oral cancer, Zhang and colleagues show that high nociceptive neuron density correlates with tumor-associated macrophage (TAM) accumulation. Cancer cells under pressure from TAMs secrete slit guidance ligand 2 (SLIT2), which activates nociceptive neurons in the TME, including some that innervate the tumor-draining lymph nodes (tdLN). Activation of those nociceptive neurons causes tdLN remodeling into an immune-suppressed state that promotes M2-like polarization of TAMs. Interrupting this inter-organ neuro-immune circuit improves the efficacy of immune checkpoint blockade.Zhang Y, …, Ji T. Cell 2025 Oct 24;188,6754–6773.e29.IL9R signaling enhances T-cell antitumor activity (from Rayray7 via Wikimedia Commons).Two studies investigate the potential of harnessing interleukin 9 (IL9) to enhance the efficacy of engineered T-cell therapy. Jiang and colleagues and Castelli and colleagues show that T cells engineered to express either a specific T-cell receptor or a chimeric antigen receptor, respectively, have enhanced antitumor activity in solid tumor preclinical models when also engineered to express the IL9 receptor (IL9R) and administered alongside exogenous IL9. IL9 signaling enhances T-cell effector phenotype and reduces dysfunction, primarily through STAT1 and STAT4. The limited natural expression of IL9R on human T cells and normal tissues suggests such IL9-based therapies could be well-tolerated, but human studies are needed.Jiang H, …, Kalbasi A. Immunity 2025 Nov 21;DOI:10.1016/j.immuni.2025.10.024.Castelli S, …, June CH. Immunity 2025 Nov 21;DOI:10.1016/j.immuni.2025.10.021.Fiber supports microbial metabolism for T-cell control of melanoma (From FDA via Wikimedia Commons).Knowledge of how microbial species impact T-cell immunity to cancer and responses to immune checkpoint blockade (ICB) therapies is still increasing. In a murine melanoma model, Bachem and colleagues provide new insight into how a high-fiber diet reduces tumor growth: it enhances microbial synthesis of the short-chain fatty acid butyrate, which in turn promotes a FOXO1-driven stem-like program in tumor-specific CD127+CD8+ T cells in the tumor-draining lymph node. Among melanoma patients, those with higher microbial-induced butyrate have elevated antitumoral CD8+ T cells and ICB responsiveness. The data suggest that diet and microbial metabolism influence ICB outcomes by regulating the differentiation of stem-like tumor-specific CD8+ T cells.Bachem A, …, Bedoui S. Immunity 2025 Nov 11;58,2799-2813.e8.MiTEs against tumor-associated macrophages (From NIAID via Wikimedia Commons).Current monotherapy approaches to targeting tumor-associated macrophages (TAMs) have shown limited efficacy. Von Locquenghien and colleagues have developed a new approach to engage myeloid, T, and natural killer (NK) cells for antitumor responses that they refer to as myeloid-targeted immunocytokines and NK/T cell enhancers (MiTEs). A MiTE comprising TREM2-targeting antagonistic antibodies fused to masked IL2 cytokines that are selectively unmasked in the tumor microenvironment by matrix metalloprotease 14, reduces tumor growth in multiple syngeneic preclinical models without inducing systemic toxicities. This is associated with remodeling of the tumor immune microenvironment. The MiTE also remodels the immune landscape of ex vivo patient-derived tumor fragments, highlighting the translational potential of the study.von Locquenghien M, …, Amit I. Cell 2025 Nov 19;188,7099–7117,e26.Ms4a7 controls cross-presentation of tumor antigens by dendritic cells (From Arcadian via Wikimedia Commons).Cross-presentation of tumor antigens by type I conventional dendritic cells (cDC1) is critical for CD8+ T-cell immunity, but how the tumor microenvironment influences this process is unclear. In a murine ovalbumin (OVA)-expressing tumor model, Xie and colleagues identify membrane-spanning 4-domains subfamily A member 7 (Ms4a7) as a regulator of cDC1 cross-presentation. Genetic deletion of Ms4a7 reduces cytokine production and migration of peptide–MHC Class I–expressing cDC1s to tumor-draining lymph nodes, reducing antigen-specific CD8+ T-cell priming, activation, and memory responses. In humans, MS4A7-expressing cDC1s correlate with antitumoral CD8+ T-cell responses and increased patient survival, providing new insight into the initiation of antitumor immunity.Xie B, …, Dong C. Science 2025 Nov 13;390,eady536.