Zhang XY, Pan XY, Zhu Y, Hu M, Ma S, Zheng SY, Wu CH, Xie YL, Xie YC. Multidimensional mechanisms of drug resistance in non-small cell lung cancer and novel strategies for overcoming it. World J Clin Oncol 2026; 17(7): 121766 [DOI: 10.5306/wjco.121766]
Corresponding Author of This Article
Yi-Chi Xie, MD, Department of Emergency, Changzhou Geriatric Hospital Affiliated to Soochow University, No. 288 Yanling East Road, Changzhou 213000, Jiangsu Province, China. xieyichi2000@163.com
Research Domain of This Article
Oncology
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review-article
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Zhang XY, Pan XY, Zhu Y, Hu M, Ma S, Zheng SY, Wu CH, Xie YL, Xie YC. Multidimensional mechanisms of drug resistance in non-small cell lung cancer and novel strategies for overcoming it. World J Clin Oncol 2026; 17(7): 121766 [DOI: 10.5306/wjco.121766]
Xiang-Yi Zhang, Min Hu, Yi-Chi Xie, Department of Emergency, Changzhou Geriatric Hospital Affiliated to Soochow University, Changzhou 213000, Jiangsu Province, China
Xiang-Yi Zhang, Yong Zhu, Shuo Ma, Si-Yan Zheng, Ci-Hang Wu, Yi-Luo Xie, Department of Clinical Medicine, Bengbu Medical University, Bengbu 233000, Anhui Province, China
Xin-Yu Pan, Department of Radiology, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215008, Jiangsu Province, China
Co-corresponding authors: Yi-Luo Xie and Yi-Chi Xie.
Author contributions: Zhang XY had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis; Xie YL and Xie YC contributed to the concept and design of the study and they contributed equally to this manuscript and are co-corresponding authors; Zhu Y, Pan XY, Hu M and Zheng SY were involved in the acquisition, analysis, and interpretation of data; Zhang XY, Ma S and Wu CH drafted the manuscript. All authors agreed to be accountable for all aspects of the work and approved the final version of the paper.
AI contribution statement: AI tools (specifically ChatGPT) were used solely for linguistic refinement and formatting assistance. No AI tool was involved in the generation of research data, interpretation of results, or formulation of conclusions. All AI-generated outputs were critically reviewed and revised by the authors.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Yi-Chi Xie, MD, Department of Emergency, Changzhou Geriatric Hospital Affiliated to Soochow University, No. 288 Yanling East Road, Changzhou 213000, Jiangsu Province, China. xieyichi2000@163.com
Received: April 1, 2026 Revised: May 17, 2026 Accepted: June 12, 2026 Published online: July 24, 2026 Processing time: 114 Days and 13.4 Hours
Abstract
Non-small cell lung cancer (NSCLC) has entered the era of precision medicine across all driver mutation subtypes and treatment settings; However, drug resistance mechanisms differ substantially across molecular subtypes and therapeutic contexts, and resistance remains a central challenge in routine clinical practice. The development of resistance is a complex, multidimensional, and spatiotemporally heterogeneous process involving the intrinsic genetic and epigenetic characteristics of tumor cells, the dynamic remodeling of the tumor microenvironment, and systemic host factors. This article summarizes the latest research advances in treatment resistance in NSCLC, delving deeply into the multidimensional nature of resistance across five dimensions: Molecular mechanisms and spatial heterogeneity, the temporal dynamics of resistance, heterogeneity of the tumor immune microenvironment, novel therapeutic strategies, and future directions for multi-omics integration. The review focuses on synergistic inhibition strategies targeting “undruggable” targets, monitoring the evolution of resistant clones via liquid biopsy, precision interventions based on immune microenvironment stratification, breakthroughs in novel therapeutic modalities such as antibody-drug conjugates, and how to utilize multi-omics data and advanced computational models to achieve personalized diagnosis and treatment. This article aims to provide a systematic theoretical framework and innovative solutions for understanding and overcoming treatment resistance in NSCLC.
Core Tip: Drug resistance in non-small cell lung cancer is not driven by single mechanisms but by a dynamic, multidimensional system shaped by clonal evolution, spatial heterogeneity, and tumor-immune interactions. This review advances a unified framework linking these dimensions and highlights how emerging strategies - including antibody-drug conjugates, bispecific antibodies, and targeted protein degradation - can overcome resistance. Integration of multi-omics and liquid biopsy is proposed as the foundation for adaptive, precision oncology.
