Reprogramming the Immune Landscape of Inflammatory Breast Cancer

ABSTRACT Inflammatory breast cancer (IBC) is the most aggressive subtype of breast cancer, characterized by rapid progression, early metastasis, and profound therapeutic resistance. Despite advances in multimodal therapy, outcomes remain poor, emphasizing the need for novel treatment strategies. Increasing evidence reveals that IBC exhibits an immunosuppressive tumor microenvironment (TME), driven by interactions among tumor cells and TME components that promote immune evasion through cytokine signaling loops, immune checkpoint overexpression, and formation of tumor emboli that shield cancer cells from immune surveillance. Recent multi‐omics and spatial transcriptomic studies reveal extensive immune heterogeneity, with both “immune‐hot” and “immune‐cold” niches influencing responses to immunotherapy. Clinical trials testing immune checkpoint inhibitors alone or combined with chemotherapy, antibody–drug conjugates, or targeted therapy show early promise but remain limited by small IBC cohorts and inconsistent diagnostic criteria. Integrating immune biomarkers, including PD‐L1 expression, tumor mutational burden, T‐cell clonality, and spatial immune signatures, may improve patient stratification and therapeutic precision. This review summarizes mechanistic and clinical insights defining IBC immunobiology, highlights barriers to durable immune activation, and outlines strategies to reprogram the TME toward an immunoactive state. Advancing combination immunotherapy and adaptive clinical trial designs through global collaboration will be essential to improve outcomes for IBC patients.