Blocking Osteoprotegerin Reprograms Cancer Associated Fibroblast to Promotes Immune Infiltration into the Tumor Microenvironment

Abstract The stromal compartment of many solid tumors plays a critical role in shaping an immunosuppressive microenvironment that limits the effectiveness of immune-based therapies 1 . Among stromal constituents, cancer-associated fibroblasts (CAFs) have emerged as key regulators of antitumor immunity 2–5 . Here, we identify a distinct subset of CAFs in both murine and human stroma-rich cancers that secrete osteoprotegerin (OPG)— a soluble decoy receptor that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL), both of which are involved in T cell function. In vitro, OPG directly impairs CD8⁺ T cell-mediated killing of target cells. In murine models of pancreatic and breast cancer, antibody-mediated blockade of OPG promotes robust immune infiltration into the tumor microenvironment, leading to significant tumor regression. Stromal profiling revealed that OPG blockade induces a shift in CAF cells—reducing immunosuppressive OPG⁺ fibroblasts while expanding interferon-responsive fibroblasts, thus recalibrating the tumor stroma toward a pro-immunogenic landscape. These findings uncover a previously unrecognized mechanism of stromal immune suppression and highlight OPG as a stromal immune checkpoint controlling CD8⁺ T cell infiltration. Targeting OPG may offer a novel therapeutic strategy to convert immunologically “cold” tumors into T cell-infiltrated, tumor microenvironment.