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Pharmaceutics
Volume 18
Issue 2
10.3390/pharmaceutics18020181
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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Review

Atlas-Guided Nanocarrier Strategies Targeting Spatial NTRK2/MAPK Signaling in EGFR-TKI-Resistant Niches of Esophageal Squamous Cell Carcinoma

by
Xiusen Zhang
1,
Xudong Zhang
1,
Xing Jin
1,
Shilei Zhang
1,
Xin Zhao
1,
Hairui Wang
1,
Hui Wang
2,
Lijun Deng
3,
Wenchao Tang
4,
Qizhi Fu
1,* and
Shegan Gao
1,5,*
1
Key Laboratory of Microbiome and Esophageal Cancer Prevention and Treatment, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
2
National Key Laboratory of Genetic Evolution & Animal Models, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650201, China
3
Zhengzhou Center for Disease Control and Prevention, Zhengzhou Health Inspection Institute, Zhengzhou 450003, China
4
Department of Critical Care Medicine, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China
5
Institute of Organoid on Chip and Drug Translation Research, Henan Academy of Sciences, Zhengzhou 450046, China
*
Authors to whom correspondence should be addressed.
Pharmaceutics 2026, 18(2), 181; https://doi.org/10.3390/pharmaceutics18020181
Submission received: 15 September 2025 / Revised: 20 November 2025 / Accepted: 9 January 2026 / Published: 30 January 2026
(This article belongs to the Section Drug Targeting and Design)
Versions Notes

Abstract

Esophageal squamous cell carcinoma (ESCC) represents a major therapeutic challenge due to the rapid development of resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Recent evidence highlights that this resistance is driven not only by genetic mutations but also by spatial heterogeneity of tumor microenvironments and compensatory signaling mechanisms. In this review, we propose a “spatial-signaling-intervention” framework with a particular focus on the NTRK2/MAPK signaling axis, which plays dual roles in signaling compensation and immune evasion. By integrating spatial multi-omics, proteomics, and AI-assisted topological modeling, three resistant niches are identified: (1) cancer stemness-enriched zones, (2) MAPK hyperactive islands, and (3) immune-cold regions. Based on this atlas, we design precision nanotherapeutic platforms, including responsive, dual-target, and feedback-loop nanocarriers, to selectively modulate resistant spatial niches. Preclinical validation in patient-derived xenografts and organoid models further demonstrates the translational potential of these strategies. This work provides a conceptual and technological roadmap for overcoming EGFR-TKI resistance in ESCC. Atlas-guided nanocarrier systems offer a promising avenue for spatially targeted and feedback-responsive therapy, highlighting the role of pharmaceutics in advancing precision oncology.
Keywords: esophageal squamous cell carcinoma; epidermal growth factor receptor-tyrosine kinase inhibitor resistance; spatial omics; NTRK2/MAPK signaling axis; intelligent nanocarrier systems; atlas-driven precision therapy esophageal squamous cell carcinoma; epidermal growth factor receptor-tyrosine kinase inhibitor resistance; spatial omics; NTRK2/MAPK signaling axis; intelligent nanocarrier systems; atlas-driven precision therapy

Share and Cite

MDPI and ACS Style

Zhang, X.; Zhang, X.; Jin, X.; Zhang, S.; Zhao, X.; Wang, H.; Wang, H.; Deng, L.; Tang, W.; Fu, Q.; et al. Atlas-Guided Nanocarrier Strategies Targeting Spatial NTRK2/MAPK Signaling in EGFR-TKI-Resistant Niches of Esophageal Squamous Cell Carcinoma. Pharmaceutics 2026, 18, 181. https://doi.org/10.3390/pharmaceutics18020181

AMA Style

Zhang X, Zhang X, Jin X, Zhang S, Zhao X, Wang H, Wang H, Deng L, Tang W, Fu Q, et al. Atlas-Guided Nanocarrier Strategies Targeting Spatial NTRK2/MAPK Signaling in EGFR-TKI-Resistant Niches of Esophageal Squamous Cell Carcinoma. Pharmaceutics. 2026; 18(2):181. https://doi.org/10.3390/pharmaceutics18020181

Chicago/Turabian Style

Zhang, Xiusen, Xudong Zhang, Xing Jin, Shilei Zhang, Xin Zhao, Hairui Wang, Hui Wang, Lijun Deng, Wenchao Tang, Qizhi Fu, and et al. 2026. "Atlas-Guided Nanocarrier Strategies Targeting Spatial NTRK2/MAPK Signaling in EGFR-TKI-Resistant Niches of Esophageal Squamous Cell Carcinoma" Pharmaceutics 18, no. 2: 181. https://doi.org/10.3390/pharmaceutics18020181

APA Style

Zhang, X., Zhang, X., Jin, X., Zhang, S., Zhao, X., Wang, H., Wang, H., Deng, L., Tang, W., Fu, Q., & Gao, S. (2026). Atlas-Guided Nanocarrier Strategies Targeting Spatial NTRK2/MAPK Signaling in EGFR-TKI-Resistant Niches of Esophageal Squamous Cell Carcinoma. Pharmaceutics, 18(2), 181. https://doi.org/10.3390/pharmaceutics18020181

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