Emerging evidence positions natural killer (NK) cells as key initiators of the inflammatory programs required for effective tumor immunity. Beyond direct tumor killing, NK cells trigger early immune responses by recruiting and activating dendritic cells (DCs), thereby enabling downstream T cell activation. However, in established tumors, NK cell–DC communication is often disrupted by metabolic stress and immunosuppressive pathways, leading to immune evasion. Here, we review advances in NK cell–DC cross-talk, cytokine-driven amplification loops and metabolic control of NK cell fitness. We propose that restoring these integrated immune ‘circuits’ may be key in converting immune-excluded tumors into immunotherapy-responsive states. Huntington et al. provide an overview of the biology and role of natural killer (NK) cells in cancer, highlighting the importance of NK cell–dendritic cell cross-talk and NK cell metabolic fitness in regulating the antitumor immune response.
Adoptive chimeric antigen receptor (CAR)-T cell therapies have limited efficacy in solid tumors because of poor infiltration and impaired effector function, whereas radiotherapy is constrained by radioresistance and metastatic spread. Here we show that integrating the spatial precision of ionizing radiation with the biological specificity of CAR-T cells enables localized delivery of the inflammatory cytokine tumor necrosis factor (TNF). We identified radiation-responsive genes in tumor-infiltrating T cells and engineered synthetic radioinducible promoters to drive TNF expression. Human CAR-T cells carrying this construct (riTNF CAR-T cells) secreted high levels of TNF upon irradiation, independently of antigen engagement. In human xenograft and murine tumor models, the combination of riTNF CAR-T cells and local irradiation produced greater tumor regression than either treatment alone or standard CAR-T cells with irradiation. This response was associated with high intratumoral, but not systemic, TNF levels, increased tumor necrosis and apoptosis, vascular disruption and greater CAR-T cell infiltration. These findings establish a platform for spatially and temporally controlled cytokine delivery from engineered CAR-T cells. Masoumi et al. engineered CAR-T cells with a radiation-inducible promoter controlling the expression and local release of the cytokine TNF upon tumor irradiation.
Basophils are rare cells best known for their role in allergy but their contribution to cancer remains poorly understood. Here, we found that basophils suppress early lung metastatic seeding in mice by enhancing antitumor CD8+ T cell immunity through inhibition of regulatory T (Treg) cells. Basophils restrain Treg cells through two complementary mechanisms: mast cell protease 8-mediated cleavage of interleukin-2 receptor α and histamine-mediated activation of the histamine H1 receptor (HRH1). HRH1 blockade with loratadine abolished Treg cell suppression and accelerated metastatic seeding in mice. In a prospective double-blind crossover trial of loratadine versus placebo enrolling 40 healthy volunteers ( IRCT20170608034390N14 ), circulating Treg cell frequency (primary outcome) increased following loratadine. Higher blood basophil counts predicted improved survival across human cancers and integrative multiomic analyses identified conserved quiescent (B0) and tumor-associated (B1) basophil states, with B0 predicting favorable outcomes. These findings identify basophils as regulators of early metastatic progression and highlight the basophil–Treg cell axis as a potential therapeutic target. Mansouri and colleagues show that basophils protect from early lung metastasis by suppressing regulatory T cells through the release of mast cell protease 8 and histamine.
Epithelial-to-mesenchymal transition (EMT) regulates tumor progression, metastasis and resistance to therapy. EMT encompasses a continuum of tumor states displaying different functions. The precise dialog between the tumor microenvironment and the different EMT states remains poorly understood. Using single-cell and spatial transcriptomics of mouse skin tumors, we uncover that different EMT states are associated with different niches. Neutrophils are more abundant in niches associated with hybrid EMT and secreted oncostatin M, which partially activates EMT while sustaining the epithelial program, promoting hybrid EMT states and metastasis formation. Macrophages are more abundant in niches associated with more advanced EMT states, which, together with other stromal cells, express TGFβ1 that promotes the late EMT state. Oncostatin M and TGFβ1 function in a feed-forward manner by creating distinct inflammatory niches to maintain specific EMT states. Together, our results reveal that distinct niches are associated with specific EMT states and that signaling pathways sustain their own niche’s identity by recruiting specific myeloid cell populations. Dong et al. conducted single-cell and spatial analyses in mouse skin tumors, revealing that myeloid-derived OSM and TGFβ1 establish distinct stromal niches that sustain hybrid and late EMT states, respectively.
Stabilization of the hybrid epithelial–mesenchymal state drives therapy resistance and metastasic progression. Dong et al. use integrated single-cell and spatial analyses to demonstrate that oncostatin M and TGFβ1, respectively, maintain hybrid and late epithelial-to-mesenchymal transition states within self-sustaining neutrophil- and macrophage-rich niches of squamous cell carcinoma.
