Targeting fibroblast derived thrombospondin 2 disrupts an immune-exclusionary environment at the tumor front in colorectal cancer.

Fibrotic colorectal cancers (CRC) are largely microsatellite-stable and display desmoplastic stroma with poor immune infiltration. Here we identify thrombospondin-2 (THBS2) as a key regulator of the immune-exclusionary phenotype in fibrotic CRC. THBS2 is highly expressed by matrix cancer-associated fibroblasts at the tumor front. In an orthotopic model using desmoplastic tumor organoids, global or fibroblast-specific Thbs2 deletion disrupts the exclusionary barrier and increases intratumoral CD8 T cells. Mechanistically, THBS2 limits recruitment of CXCR3+ CD8 T cells by restraining dendritic- and macrophage-derived CXCL9/10. Depletion of these myeloid cells or blockade of CXCL9/10-CXCR3 signaling abolishes the enhanced CD8 T-cell influx and antitumor efficacy. Spatial profiling demonstrates that THBS2 loss induces proximity between CD8 T cells and myeloid cells and upregulates chemokines. Despite increased infiltration, CD8 T cells manifest exhaustion, rendering tumors highly susceptible to immune checkpoint blockade. THBS2 thus represents a tractable CAF-restricted target to overcome immune exclusion in fibrotic CRCs.