C-type lectin domain family 5 member A-mediated activation of macrophages via a bispecific antibody enhances anti-HER2 therapy

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	C-type lectin domain family 5 member A-mediated activation of macrophages via a bispecific antibody enhances anti-HER2 therapy
	Hou, L; Jiao, DC; Dai, H; Zhang, JY; Wang, LN; Gong, XL; Qi, CH; Guo, XH; Liu, ZZ
	2026
发表期刊	J. Immunother. Cancer
卷号	14 期号:4
摘要	Background Although HER2-targeted therapies have dramatically improved outcomes for patients with HER2-positive breast cancer, the immunosuppressive tumor microenvironment remains a major barrier to effective immunotherapy in this subtype. Therefore, we sought to develop a new bispecific antibody targeting both HER2 and C-type lectin domain family 5 member A (CLEC5A), a pattern recognition receptor on innate immune cells like macrophages, aiming to alter the tumor immune environment.Methods CLEC5A-HER2 bispecific antibodies were generated and evaluated for binding properties, macrophage activation, and phagocytic activity in vitro. Anti-tumor efficacy was assessed in multiple syngeneic mouse models, including orthotopic breast cancer models, with mechanistic studies and immune checkpoint inhibitor combinations.Results The CLEC5A-HER2 bispecific antibody was more effective in anti-tumor activity than either monotherapies or combinations of individual antibodies in various syngeneic models, including an orthotopic breast cancer model. Mechanistically, it converted cold tumors into hot tumors by promoting macrophage-mediated phagocytosis, repolarizing tumor-associated macrophages toward an M1-like phenotype, and enhancing antigen presentation and T-cell recruitment. This immune remodeling restored the CXCL9/10-CXCR3 axis, increased CD8+ T cell infiltration, reduced regulatory T cells, and underpinned a T cell-dependent anti-tumor response. Interestingly, combination therapy with CTLA-4 and PD-1 blockade exhibited strong synergistic effects without significant toxicity.Conclusions These results identify the CLEC5A-HER2 bispecific antibody as a potential immunotherapy for HER2-positive cancers by effectively engaging both innate and adaptive immunity.
收录类别	SCIE
语种	英语
文献类型	期刊论文
条目标识符	http://ir.kiz.ac.cn/handle/152453/15032
专题	科研部门_鸟类学（杨晓君）
推荐引用方式 GB/T 7714	Hou, L,Jiao, DC,Dai, H,et al. C-type lectin domain family 5 member A-mediated activation of macrophages via a bispecific antibody enhances anti-HER2 therapy[J]. J. Immunother. Cancer,2026,14(4).
APA	Hou, L.,Jiao, DC.,Dai, H.,Zhang, JY.,Wang, LN.,...&Liu, ZZ.(2026).C-type lectin domain family 5 member A-mediated activation of macrophages via a bispecific antibody enhances anti-HER2 therapy.J. Immunother. Cancer,14(4).
MLA	Hou, L,et al."C-type lectin domain family 5 member A-mediated activation of macrophages via a bispecific antibody enhances anti-HER2 therapy".J. Immunother. Cancer 14.4(2026).

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