Distinct immune microenvironment in HER2-low triple-negative breast cancer underlies inferior response to immunotherapy

Effective predictive biomarkers for immunotherapy in breast cancer remain elusive, limiting precision treatment strategies. Although the biological significance of HER2‑low expression has gained increasing attention, its impact on immunotherapy response remains unknown. Here, we investigated the impact of HER2 expression on response to neoadjuvant immunotherapy in triple-negative breast cancer (TNBC) and explored the underlying biological patterns through comprehensive multi-omics analysis. A multi-center real-world cohort study revealed that HER2-low TNBC patients had poorer responses to immunotherapy than HER2-0 patients, whereas no significant difference was observed in chemotherapy alone; these findings were validated in independent prospective cohorts (ISPY-2 and NeoTRIP). Single‑cell multi‑omics further demonstrated that HER2‑low tumors exhibited reduced expression of major histocompatibility complex and immune checkpoint molecules, along with diminished T‑cell activity, relative to HER2‑0 tumors. Following immunotherapy, HER2‑low tumors showed no significant downregulation of targeted immune checkpoint molecules and less pronounced T‑cell clonal remodeling. Collectively, these findings establish HER2‑low expression as a negative predictor of immunotherapy response, shaped by a less immunogenic tumor microenvironment. These results provide important insights into the distinct immunological features of HER2‑low triple‑negative breast cancer and warrant further mechanistic and clinical investigations.