Dendritic cell PD-L2 restrains intratumoral CD8 + T cell immunity.

Blockade of inhibitory PD-1 signaling on T cells is a cornerstone of cancer immunotherapy, with current strategies targeting PD-1 or its ligand PD-L1. However, PD-1 engages an alternative ligand, PD-L2, whose role in tumor immunity remains poorly defined. Here, we show that PD-L2 is upregulated on intratumoral CCR7⁺ conventional dendritic cells (cDCs) in both mouse and human melanoma. Using genetic mouse models enabling selective ablation of PD-L1 or PD-L2 in cDCs, we identify a division of labor between these ligands: PD-L1 controls the size of the progenitor CD8⁺ T cell pool in tumor-draining lymph nodes by modulating stem-like CD8⁺ T cells, whereas PD-L2 limits progenitor exhausted CD8 + T cell differentiation within the tumor microenvironment. Loss of PD-L2 in cDCs enhances cytotoxic CD8⁺ T cell responses and suppresses tumor growth, particularly in tumors enriched for CCR7⁺ cDC1s. Consistent with this, increased CCR7 + cDC abundance is associated with poor prognosis in human cancers. Spatial transcriptomic analyses reveal co-localization of CCR7⁺ cDC1s and Tpex within CCL19 hi niches, where cancer-associated fibroblasts serve as the predominant source of CCL19. Finally, intratumoral GM-CSF drives PD-L2 expression on CCR7⁺ cDCs, with Tpex and NK cells as major sources. Together, these findings establish cDC- associated PD-L1 and PD-L2 as spatially and functionally distinct checkpoints governing CD8⁺ T cell differentiation. Our results suggest that the abundance of CCR7⁺PD-L2⁺ cDC1s may guide the choice between anti-PD-1 and anti- PD-L1 therapies and support the development of PD-L2-directed blockade.