Macrophage-Dendritic Cell-T-Cell Tetrads Orchestrate Antitumor Immunity and Response to Checkpoint Blockade

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Immune checkpoint inhibitors (ICIs) elicit durable responses in only a subset of patients with solid tumors, underscoring the need to define the cellular architectures that govern effective antitumor immunity. Here we identify a spatially organized multicellular immune unit comprising macrophages, cDC1s, CD4⁺ T-cells, and CD8⁺ T-cells that emerges in response to anti-CTLA-4 or dual checkpoint blockade. We term these structures tetrads . Using multiplexed imaging and spatial transcriptomics in mouse and human tumors, we show that tetrads assemble early during immune priming, depend on the ICOS–ICOSL pathway, and are enriched for ICOS⁺ Th1-like CD4⁺ T cells and ICOSL high cDC1s. CD8⁺ T-cells within tetrads exhibit an activated, non-terminally differentiated state, while tetrad-associated macrophages display an interferon-γ–responsive program that sustains CD8⁺ T-cell function and prevents dysfunction. Functionally, ICOSL⁺ cDC1s are required for tumor eradication in vivo . In patients with bladder cancer treated with neoadjuvant dual checkpoint blockade, tetrad, but not triad or dyad formation correlates with clinical response. These findings establish tetrads as a fundamental cellular unit coordinating antitumor immunity and responsiveness to ICIs.