Potentiating dendritic cell immunotherapy by interrupting the Semaphorin 4D-induced immune-suppressive barrier

Immune suppression within the tumor microenvironment (TME) remains a significant barrier to effective cancer immunotherapy, including dendritic cell (DC)-based approaches. We address this by targeting Semaphorin 4D (SEMA4D), a pro-tumorigenic mediator expressed by leading-edge tumor cells and host immune cells, particularly in HER2-positive (HER2^pos) breast cancer (BC). Antibody blockade of SEMA4D enhances the efficacy of adoptively transferred tumor-specific conventional type 1 DCs (cDC1s) across multiple HER2^pos BC models. Tumor-cell-specific ablation of SEMA4D activity amplifies cDC1-driven anti-tumor immunity, highlighting its role in immune evasion. SEMA4D blockade synergizes with cDC1s to increase CD4⁺ Th1 and other effector cell infiltration into the TME, along with reciprocal elimination of myeloid-derived suppressor cells, fostering robust systemic immune responses that eradicated both local and distant tumors. Given its favorable safety profile, this strategy represents a promising immunotherapy for malignancies, including HER2^pos BC that express high levels of SEMA4D in both tumor and stromal compartments.