Ibanez Molero, S.; Coccimiglio, M.; Olivia Springer, B.; Bowien de Ruiter, M.; Clayton, G.; Wijnen, S.; Blank, C.; Labots, M.; de Gruijl, T.; van Kooyk, Y.

Antigen-presenting cell (APC) interactions with cytotoxic T cells are critical for anti-tumour immunity and response to immune checkpoint blockade (ICB), yet context-specific regulators in the tumour microenvironment remain not fully defined. Here we identify the lectin receptor SIGLEC1 as a key mediator of macrophage-T cell interactions in human melanoma. In a well-characterized patient cohort, SIGLEC1 was selectively upregulated in inflammatory macrophages physically associated with activated/exhausted CD8+T cells. Imaging and functional analyses revealed that SIGLEC1 accumulates at the macrophage-T cell interface and promotes cell clustering. SIGLEC1 ligands were enriched on activated T cells, and their blockade reduced cytotoxic cytokine production ex vivo. Single-cell (spatial) transcriptomics across independent ICB-treated melanoma cohorts showed that SIGLEC1+ macrophages localize near CD8+T cells and are enriched in responders, where they also associate with T cells expressing activation/exhaustion markers. These findings define a SIGLEC1-dependent macrophage-T cell niche linked to effective immunotherapy.