Dendritic Cells Establish and Maintain Tertiary Lymphoid Structure and Function

Tertiary lymphoid structures (TLS), which are organized aggregates of T cells, B cells, and stromal elements that arise within tumors, are associated with improved outcomes and stronger responses to immune checkpoint blockade across multiple cancer types. However, the cellular drivers that establish and sustain these structures have remained poorly defined, particularly the role of antigen-presenting dendritic cells (DC) within them. Mattiuz and colleagues set out to determine which DC subsets control TLS formation versus long-term maintenance and whether antigen presentation to CD4+ and CD8+ T cells underlies these processes. Using spatial transcriptomics and multiplex imaging analysis of patient samples of non–small cell lung cancer, hepatocellular carcinoma, and other tumor types alongside an orthotopic lung cancer mouse model engineered to reliably generate mature TLSs, the team employed genetic strategies to selectively eliminate type 1 conventional dendritic cells (cDC1) or specific antigen-presentation and migration pathways at defined stages of tumor progression. Early TLS formation was found to depend on IFNγ-driven cDC1 maturation and migration to tumor-draining lymph nodes, whereas, once TLSs matured, their persistence became independent of lymph node egress and instead relied on cDC1 accumulation within intratumoral CCR7 ligand–rich stromal niches. There, concomitant MHC-I and MHC-II antigen presentation by cDC1s, together with CD40 signaling, was required to preserve T follicular helper cells, sustain germinal center reactions, support tumor-specific antibody production, and drive progenitor exhausted CD8+ T-cell differentiation. Depleting cDC1s after TLSs had already formed disrupted their architecture and worsened survival in tumor-bearing mice, while expanding DCs with FLT3L or CD40 agonists enlarged TLSs. These findings position cDC1s as central, stage-specific orchestrators of antitumor immunity and suggest that therapies boosting intratumoral DC abundance or activation could enhance TLS-driven immune responses and improve outcomes with checkpoint blockade.Mattiuz R, Boumelha J, Aerakis E, Le Berichel J, Hamon P, Halasz L, et al. Dendritic cells control tertiary lymphoid structure development and maintenance in cancer. Science 2026;393:eady1678.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.