Aug 2026· Current Issues in Molecular Biology· 0 citations· 165 references
TL;DR
The rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation are discussed.
Abstract
Lung cancer is currently the most frequently diagnosed malignancy worldwide, accounting for approximately 12.4% of all cancers and, despite major advances in molecularly targeted therapies and immunotherapy, represents the leading cause of cancer-related mortality, In recent years, antibody–drug conjugates (ADCs) have emerged as a novel therapeutic strategy, combining the specificity of monoclonal antibodies with the potent cytotoxic activity of highly active payloads to selectively target tumor cells while limiting systemic toxicity. This narrative review summarizes the current role of ADCs in lung cancer, with particular focus on their structural components, mechanisms of action, and the biological features that determine treatment efficacy. We discuss the rationale for targeting established and emerging antigens in non-small cell and small cell lung cancer, including HER2, TROP2, c-MET, HER3, CEACAM5, DLL3, and other promising targets currently under clinical investigation. The principal mechanisms of primary and acquired resistance are also reviewed, including antigen modulation, altered intracellular trafficking, lysosomal dysfunction, drug efflux, tumor microenvironment-mediated immune suppression, and intratumor heterogeneity. In addition, we provide an overview of the safety profile of ADCs, highlighting the most clinically relevant adverse events and their underlying biological mechanisms. We also examine the evolving landscape of predictive biomarkers beyond antigen expression, including genomic, transcriptomic, proteomic, and liquid biopsy-based approaches, together with emerging spatial and single-cell technologies that may improve patient selection. Finally, we discuss future directions in the field, including novel payloads, next-generation linker technologies, bispecific ADCs, combination strategies, and personalized ADC development. Overall, ADCs are rapidly reshaping the therapeutic landscape of lung cancer. Continued optimization of drug design, biomarker-driven patient selection, and a deeper understanding of resistance mechanisms will be essential to fully realize their clinical potential.
Overall, the results suggest that despite the challenges, this technology represents a significant advance in breast cancer therapy and that the integration of combined and personalized strategies may enhance antibody efficacy, overcome current barriers and contribute to better clinical outcomes.
A. D. da Cruz, M. Lima, Bárbara Sentanin et al.· International Journal of Adv...· 0 citations
Future research should prioritize tumor-selective linker design, novel payload development, bispecific and dual-payload ADC platforms, and rational combination strategies to overcome resistance and further improve the therapeutic index of ADCs in CRC.
L. Zeng, Yuanlin Zhu, Ke Zhang et al.· Biochemical Pharmacology· 0 citations
Antibody–drug conjugates (ADCs) represent a transformative therapeutic class in non-small cell lung cancer (NSCLC), moving precision oncology beyond traditional targeted therapies. These agents, composed of a monoclonal antibody, linker, and potent cytotoxic payload, enable targeted drug delivery to tumor cells expressing specific antigens like TROP2, HER2, and c-MET. Recent clinical trials have demonstrated remarkable efficacy of ADCs, both as monotherapy in molecularly defined populations and in combination with immunotherapy, offering new hope for patients with advanced disease. This review summarizes the latest clinical progress of ADCs in NSCLC, highlighting key agents and their impact, while also addressing the associated challenges and future directions for optimizing this promising treatment modality.
Xi Chen, Sirui Wu, Feiyang Li et al.· Holistic Integrative Oncolog...· 0 citations
This review synthesizes literature spanning 1990-2026 on advances in ADC design and their clinical and translational implementation in breast cancer to support reframing antigen selection as a system-level challenge, supported by delivery-focused engineering, precision-medicine-driven trial design, and adaptive methodology.
Callum Chapman, A. Cheung, G. B. Armstrong et al.· Expert Opinion on Drug Deliv...· 0 citations
Due to high incidence, aggressive progression, and limited therapeutic efficacy, lung, pancreatic, and colorectal cancer represent a significant share of cancer-related deaths. Cancer remains a major cause of global morbidity and mortality. Despite considerable progress in traditional treatments such as surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, challenges like drug resistance, systemic toxicity, tumor heterogeneity, and recurrence continue to hinder long-term success. Therefore, the identification, study, and creation of new chemical compounds have become a promising approach to improving cancer treatment outcomes. By integrating current knowledge on chemical compound development and mechanistic insights across these three major cancer types, this review identifies existing research gaps, summarizes recent therapeutic advances, and outlines future directions for the rational design of safer and more effective anticancer agents. The findings presented herein are expected to support researchers and clinicians in advancing precision oncology and developing next-generation therapeutics for improved patient outcomes. With cancer being the rising cause of morbidity and mortality in the world today challenges the global health systems. Cancer is often diagnosed at advanced stages and possesses poor prognosis due to cancer having high metastatic potential and limited response to treatment therapies. The process of oncology despite extensive advancement such as chemotherapy regimens faces issues of drug resistance, systemic toxicity and lack of ability to detect tumor specificity. This review provides a comprehensive overview of recent advances in the development of chemical compounds targeting lung, pancreatic, and colorectal cancers. It discusses the structural diversity, biological activities, and molecular mechanisms of natural products, synthetic molecules, and semisynthetic derivatives with demonstrated anticancer potential. Particular emphasis is placed on their interactions with key signaling pathways involved in tumor initiation and progression.
Peer Review History:
Received 7 April 2026; Reviewed 11 May 2026; Accepted 9 June; Available online 15 July 2026
Academic Editor: Prof. Cyprian Ogbonna ONYEJI, Obafemi Awolowo University, Ile-Ife, Nigeria, conyeji@oauife.edu.ng
Reviewers:
Dr. Fátima Morales Marín, University of Murcia, Spain, fatima.morales@um.es
Dr. George Zhu, Tehran University of Medical Sciences, Tehran, Iran, sansan4240732@163.com
N. Zaidi· Universal Journal of Pharmac...· 0 citations
