SPP1-positive macrophages drive trastuzumab resistance in HER2-positive breast cancer.

Authors

Donghui Wang, Guodong Li, Yajie Lu, Ruoxin Du, Xiangmei He, Jiahui Sun, Danxi Li, Siyuan Wang, Yimin Liu, Shuning Wang, Lan Hou, Juliang Zhang, Yuan Gao, Cun Zhang

Published in

Cell communication and signaling : CCS. Jul 17, 2026. Epub Jul 17, 2026.

Abstract

Trastuzumab-based HER2-targeted therapy remains the cornerstone treatment for HER2-positive breast cancer. However, its clinical efficacy is significantly modulated by the tumor microenvironment (TME). Our single-cell sequencing analysis of clinical samples revealed that patients with poor radiologic response after trastuzumab-based neoadjuvant therapy presented significant enrichment of TIGIT⁺ NK cells with high immune checkpoint expression, exhausted CD8⁺ T cells, and immunosuppressive regulatory T cells (Tregs). Further analyses leveraging cell-cell communication, spatial transcriptomics, and multiplex immunofluorescence showed that SPP1⁺ tumor-associated macrophages (SPP1⁺ TAMs) enrichment was associated with dysfunctional NK- and T-cell states in tumors from patients with poor radiologic response. Functional validation studies revealed that SPP1⁺ TAMs actively induced exhaustion phenotypes in both NK cells and CD8⁺ T cells, thereby impairing trastuzumab-dependent antibody-dependent cellular cytotoxicity (ADCC) and adaptive immune responses. In vivo experiments using humanized NCG murine models further confirmed the SPP1⁺ TAMs-mediated suppression of NK cell function. Significantly, HER2-positive breast cancer patients with elevated SPP1⁺ TAMs levels experienced both reduced efficacy of trastuzumab neoadjuvant therapy and diminished long-term survival prospects. In summary, our findings provide the first systematic characterization of TME remodeling following trastuzumab therapy, identifying SPP1⁺ TAMs as a potential driver of trastuzumab resistance. This work advances our understanding of microenvironmental mechanisms underlying trastuzumab resistance and suggests new therapeutic strategies targeting TAM-mediated immunosuppression.

PMID:
42469833
Bibliographic data and abstract were imported from PubMed on 18 Jul 2026.

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