Collagen‐Binding IL‐15 Immunocytokine Armed Oncolytic Adenovirus Establishes a Self‐Reinforcing Immunostimulatory Milieu to Potentiate Antitumor Immunity

ABSTRACT The immunosuppressive microenvironment limits immunotherapy in triple‐negative breast cancer (TNBC). Interleukin‐15 (IL‐15) activates cytotoxic lymphocytes but is limited by rapid clearance and poor tumor retention. Here, we developed an oncolytic adenovirus encoding IL15C‐CBD, an immunocytokine comprising an IL‐15/IL‐15Rα sushi‐domain complex fused to a collagen‐binding domain, thereby establishing a self‐reinforcing immunostimulatory milieu within tumors. Intratumoral administered OV‐IL15C‐CBD lyses tumor cells and secretes IL15C‐CBD that anchors to extracellular matrix collagens, forming a localized cytokine reservoir. In the murine 4T1 TNBC model, this strategy profoundly remodeled the microenvironment by recruiting CD8 + T cells and natural killer cells, depleting regulatory T cells, and polarizing macrophages. toward an M1‐like phenotype. Consequently, OV‐IL15C‐CBD induced significant tumor regression and extended survival without evident systemic toxicity. This therapeutic advantage was further validated in the EMT6 breast tumor model, yielding consistent antitumor efficacy and prolonged survival. Collectively, anchoring immunocytokines to the tumor stroma via oncolytic viruses provides a potentially safe and effective localized immunotherapy for TNBC.