Treatment options after tumor resistance: exploiting vulnerabilities from genome to tumor microenvironment.
6 affiliations
- 1Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
- 2Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
- 3Institute of Clinical Medicine, National Infrastructures for Translational Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
- 4Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. [email protected].
- 5Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. [email protected].
- 6Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China. [email protected].
Abstract
Most advanced cancers eventually develop therapeutic resistance, often considered as a clinical endpoint but can be interpreted as an evolutionary state that exposes newly acquired dependencies and therefore creates a rationale for vulnerability-based treatment after standard options fail. This review summarizes resistance-associated vulnerabilities across genomic, epigenomic, signaling, cellular, and microenvironmental layers. At the genomic level, homologous recombination deficiency, deficient mismatch repair, chromosomal instability, and replication stress can inform DNA repair-directed, checkpoint-targeting, or immune-based strategies with different clinical evidence levels. At the epigenomic level, we propose chromatin-state maintenance vulnerability as an organizing concept describing adaptive dependence on chromatin-regulatory programs sustaining resistant phenotypes. This concept shifts epigenetic targeting away from isolated epigenetic marks to the machinery required to maintain a resistant phenotype. Compensatory signaling creates dependencies on specific network nodes, providing a rationale for combinations that suppress the pathways required for resistant-cell survival. Cancer stemness links molecular adaptations to persistent disease; interactions with a therapy-remodeled microenvironment create opportunities for intervention beyond direct tumor-cell killing. In this setting, therapeutic vulnerability may lie in reprogramming the surrounding ecosystem to restore antitumor immunity and treatment responsiveness. Additionally, we propose the concept of operational vulnerability biomarkers as measurements linked to a treatment-relevant dependency or functional susceptibility and a prespecified therapeutic decision. This decision-oriented framework complements established functional and dynamic biomarker concepts. By connecting resistant states with measurable dependencies, matched interventions, and clinical-trial strategies, the review provides a practical framework for developing and testing rational subsequent-line treatments while addressing the biological, analytical, and practical barriers to implementation.
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BibTeX
@article{li2026treatment,
title = {{Treatment options after tumor resistance: exploiting vulnerabilities from genome to tumor microenvironment.}},
author = {Jiongyuan Li and Nan Zhang and Mingjian Piao and Jiayi Zhao and Yiming Wang and Chengjie Li and Shuofeng Li and Ziyue Huang and Yiran Li and Ziyu Xun and Huishan Sun and Hanping Wang and Xiaobo Yang and Haitao Zhao},
journal = {Cancer metastasis reviews},
year = {2026},
month = oct,
doi = {10.1007/s10555-026-10392-5},
url = {https://europepmc.org/article/MED/42955439},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Treatment options after tumor resistance: exploiting vulnerabilities from genome to tumor microenvironment.
AU - Jiongyuan Li
AU - Nan Zhang
AU - Mingjian Piao
AU - Jiayi Zhao
AU - Yiming Wang
AU - Chengjie Li
AU - Shuofeng Li
AU - Ziyue Huang
AU - Yiran Li
AU - Ziyu Xun
AU - Huishan Sun
AU - Hanping Wang
AU - Xiaobo Yang
AU - Haitao Zhao
PY - 2026
DA - 2026/10/29
JO - Cancer metastasis reviews
DO - 10.1007/s10555-026-10392-5
UR - https://europepmc.org/article/MED/42955439
AB - Most advanced cancers eventually develop therapeutic resistance, often considered as a clinical endpoint but can be interpreted as an evolutionary state that exposes newly acquired dependencies and therefore creates a rationale for vulnerability-based treatment after standard options fail. This review summarizes resistance-associated vulnerabilities across genomic, epigenomic, signaling, cellular, and microenvironmental layers. At the genomic level, homologous recombination deficiency, deficient mismatch repair, chromosomal instability, and replication stress can inform DNA repair-directed, checkpoint-targeting, or immune-based strategies with different clinical evidence levels. At the epigenomic level, we propose chromatin-state maintenance vulnerability as an organizing concept describing adaptive dependence on chromatin-regulatory programs sustaining resistant phenotypes. This concept shifts epigenetic targeting away from isolated epigenetic marks to the machinery required to maintain a resistant phenotype. Compensatory signaling creates dependencies on specific network nodes, providing a rationale for combinations that suppress the pathways required for resistant-cell survival. Cancer stemness links molecular adaptations to persistent disease; interactions with a therapy-remodeled microenvironment create opportunities for intervention beyond direct tumor-cell killing. In this setting, therapeutic vulnerability may lie in reprogramming the surrounding ecosystem to restore antitumor immunity and treatment responsiveness. Additionally, we propose the concept of operational vulnerability biomarkers as measurements linked to a treatment-relevant dependency or functional susceptibility and a prespecified therapeutic decision. This decision-oriented framework complements established functional and dynamic biomarker concepts. By connecting resistant states with measurable dependencies, matched interventions, and clinical-trial strategies, the review provides a practical framework for developing and testing rational subsequent-line treatments while addressing the biological, analytical, and practical barriers to implementation.
SN - 0167-7659
SN - 1573-7233
ER -