Tumor-to-dendritic cell reprogramming induces immunogenic lymphoid structures across cancers

Tertiary lymphoid structures (TLSs) in tumors are associated with improved responses to immunotherapy. Here, we examined the impact of type 1 conventional dendritic cells (cDC1s) in TLS formation. Reprogrammed tumor cells into cDC1-like cells remodeled the tumor microenvironment and induced immunogenic TLSs (imgTLSs) across melanoma, colon, bladder, breast, and pancreatic cancer models with distinct genetic backgrounds. cDC1-like cells activated lymphotoxin, TNF, and interferon programs and engaged early with T cells through MHC class I and CD40 signaling to induce imgTLSs containing BCL6 + germinal centers, independently of endogenous cDC1s. Intratumoral positioning shaped distinct cDC1-like cell states, with DC-LAMP + CCR7 + migratory cDC1s nucleating niches enriched in CD4 + , CD8 + T cells, and B cells in mouse and human tumors. ImgTLSs sustained B and T cell responses and promoted systemic immunity through expansion of shared clonotypes in distant, untreated tumors. Our findings outline the spatial organization, signaling programs and interactions of cDC1-like cells that initiate intratumoral lymphoid structures and establish cellular reprogramming as a strategy toward overcoming resistance to immunotherapy.