HER2-low breast cancer is immune-cold: insights into tumor-infiltrating immune cells and implications for immunotherapy

This study investigated, for the first time, the association between HER2 expression, immune infiltration inferred by CIBERSORTx, and immunotherapy response in HER2-negative early breast cancer (EBC). Gene expression was analyzed in prospective discovery ( n = 104), confirmatory ( n = 81), and independent (ABiM, n = 318) cohorts. HER2 expression was measured using a 20-gene signature yielding progressively higher scores from HER2-0 to HER2-low, as routinely defined. Increased HER2 expression was consistently associated with reduced immune-infiltration, especially cytotoxic (CD8 + ) T cells and M1 macrophages; and hormone receptor (HR)-specific depletions with significant interactions for mast cells resting and neutrophils. In analysis of covariance, HER2 expression independently predicted low B-naïve and plasma cell abundance. In a neoadjuvant immunotherapy real-world cohort ( n = 111), HER2-low primary tumors had lower midcourse (28% vs. 44%) and pathological complete response (64% vs. 72%) compared to HER2-0. These findings show that HER2 expression defines immune-cold HER2-negative EBC, hindering immunotherapy and supporting HER2-targeted combination in HER2-low EBC patients.