Transforming growth factor β (TGF-β) accumulation in the tumor microenvironment (TME) is a major barrier to durable antitumor immunity. We developed fibronectin extra domain B (FN-EDB)-binding peptide (FEBP)-soluble TβRII-Fc (sTβRII), an engineered inhibitor targeting the FN-EDB-rich tumor matrix for localized TGF-β blockade. In fibrotic, immune-excluded tumors, FEBP-sTβRII suppresses TGF-β/SMAD signaling to unleash T cell activation and IFN-γ production, thereby driving feedforward cancer-associated fibroblast (CAF)-myeloid reprogramming toward an antigen-presenting state. This coordinated remodeling relieves immune exclusion and converts the fibrotic TME into an antigen-visible ecosystem that sustains robust T cell infiltration and activation. Consequently, FEBP-sTβRII induces T cell-dependent tumor regression, expands effector-memory populations, and elicits long-term, cross-protective antitumor immunity, while minimizing peripheral transcriptional disturbances compared with systemic sTβRII. Together, these findings show that spatially targeted TGF-β blockade overcomes fibrotic immune exclusion to establish durable local and systemic tumor immunity.
