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Peer-reviewedCC BY-NCDrug design, development and therapy

CEACAM5-Targeted Therapies in Solid Tumors: Biological Barriers and Next-Generation Precision Strategies.

  • Tingting Ye1
  • Ruohan Mei2
  • Xiaoting Liu2
  • Panpan Huang1
  1. 1School of Basic Medicine, Gannan Medical University, Ganzhou, Jiangxi, 341000, People's Republic of China.
  2. 2The First Clinical Medical College, Gannan Medical University, Ganzhou, Jiangxi, 341000, People's Republic of China.
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Abstract

Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is an attractive therapeutic target because of its widespread overexpression in epithelial malignancies and its polarised, largely luminal expression in normal epithelium. Despite extensive clinical development, no CEACAM5-targeted drug has received regulatory approval. The Phase III CARMEN-LC03 trial highlighted the limitations of expression-based patient selection, as tusamitamab ravtansine failed to improve the ORR over docetaxel in patients with high CEACAM5 expression. This review argues that progress in CEACAM5-targeted therapy requires a shift from focusing solely on target expression to understanding the target's biological constraints. We first summarize the biological functions of CEACAM5 in tumor progression, then discuss the major biological barriers limiting therapeutic efficacy including GPI anchor-mediated slow internalization, soluble CEACAM5-mediated antigen sink effects, extensive glycosylation, antigen heterogeneity, and immunosuppressive tumor microenvironment. Building on these biological barriers, we outline five priorities for next-generation development: targeting tumor-specific glycoforms, multi-antigen strategies, microenvironment remodeling, conditionally restricted delivery, and biomarker-guided clinical trial design. Future patient selection should integrate CEACAM5 expression with target biology and therapeutic modality compatibility to identify patients likely to benefit and reduce ineffective treatment.

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Cite

BibTeXRIS
BibTeX
@article{ye2026ceacam5targeted,
  title = {{CEACAM5-Targeted Therapies in Solid Tumors: Biological Barriers and Next-Generation Precision Strategies.}},
  author = {Tingting Ye and Ruohan Mei and Xiaoting Liu and Panpan Huang},
  journal = {Drug design, development and therapy},
  year = {2026},
  month = nov,
  doi = {10.2147/dddt.s650566},
  url = {https://europepmc.org/article/MED/42999607},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - CEACAM5-Targeted Therapies in Solid Tumors: Biological Barriers and Next-Generation Precision Strategies.
AU  - Tingting Ye
AU  - Ruohan Mei
AU  - Xiaoting Liu
AU  - Panpan Huang
PY  - 2026
DA  - 2026/11/03
JO  - Drug design, development and therapy
DO  - 10.2147/dddt.s650566
UR  - https://europepmc.org/article/MED/42999607
AB  - Carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) is an attractive therapeutic target because of its widespread overexpression in epithelial malignancies and its polarised, largely luminal expression in normal epithelium. Despite extensive clinical development, no CEACAM5-targeted drug has received regulatory approval. The Phase III CARMEN-LC03 trial highlighted the limitations of expression-based patient selection, as tusamitamab ravtansine failed to improve the ORR over docetaxel in patients with high CEACAM5 expression. This review argues that progress in CEACAM5-targeted therapy requires a shift from focusing solely on target expression to understanding the target's biological constraints. We first summarize the biological functions of CEACAM5 in tumor progression, then discuss the major biological barriers limiting therapeutic efficacy including GPI anchor-mediated slow internalization, soluble CEACAM5-mediated antigen sink effects, extensive glycosylation, antigen heterogeneity, and immunosuppressive tumor microenvironment. Building on these biological barriers, we outline five priorities for next-generation development: targeting tumor-specific glycoforms, multi-antigen strategies, microenvironment remodeling, conditionally restricted delivery, and biomarker-guided clinical trial design. Future patient selection should integrate CEACAM5 expression with target biology and therapeutic modality compatibility to identify patients likely to benefit and reduce ineffective treatment.
SN  - 1177-8881
ER  -