Reprogramming the Tumor Immune Microenvironment with ICAM‐1‐Targeted Antibody‒Drug Conjugates and B7‐H3‐CD3 Bispecific Antibodies

Abstract Reprogramming the tumor immune microenvironment (TIM) plays an important role in promoting the reversal of immune “cold” tumors into “hot” inflammatory tumors. Improving drug targeting, blocking immune checkpoints, and promoting the activation of immune cells are crucial for reprogramming the TIM. Here, an intercellular adhesion molecule 1‐targeted antibody‒drug conjugate in combination with a B7‐H3‐CD3 bispecific antibody is selected for TIM reprogramming, which improved the efficacy of triple‐negative breast cancer immunotherapy. This combination therapy improves drug targeting, blocks immune checkpoint pathways, and activates effector T cells to release cytokines, leading to immunogenic cell death and the release of tumor‐associated antigens. This effect promotes the maturation of dendritic cells, infiltration and activation of cytotoxic CD8+ T cells, repolarization of M1‐type macrophages, and reduction of M2‐type macrophages, immune suppressor Tregs, and MDS cells, thereby reprogramming the TIM. In addition, this innovative strategy promotes the accumulation of immune cells at metastasis sites and significantly impedes the progression of lung metastatic lesions. Overall, this study provides novel insights for reprogramming the TIM using novel immunotherapeutic strategies that leverage the synergistic effects of antibody‐drug conjugates and bispecific antibodies.