A matrikine organizes the dendritic cell- T cell triads that build tertiary lymphoid structures

Tertiary lymphoid structures (TLS) predict checkpoint-inhibition response, and conventional dendritic cells (cDC) are required to build and maintain them. What licenses tumor niches is not fully understood: chemokines recruit cells but do not specify TLS-archetypal DC:CD4+T:CD8+T triad composition. We show that the organizing signal is a matrix fragment. Proteoglycan versican (VCAN) proteolysis releases the matrikine versikine constitutively in CXCL13-replete germinal center light zones. In tumors, versikine is released inducibly within CXCL13-rich stromal niches. Versikine activates CD11b+ cDC, expands cDC1, and suffices for triad assembly. Versikine-conditioned DC engage progenitor-exhausted CD8+ T-cells (Tpex) and Tpex-sustaining, Th1-polarized follicular helper CD4+ T-cells. Excess unproteolyzed VCAN inverts this toward DC-Treg crosstalk and Tpex loss. Versikine (mRNA or recombinant protein) plus anti-PD-L1 eradicated experimental tumors reverse-translated to model adverse-prognosis, VCAN-proteolysis-weak patients from a prospective PD-1 blockade trial in oligometastatic colorectal cancer. The extracellular matrix instructs, rather than merely scaffolds, the multicellular units of antitumor immunity.