Molecular Adaptation Mechanisms Driving Therapy Resistance in Gastrointestinal Malignancies

Gastrointestinal malignancies, including gastric cancer, colorectal cancer, pancreatic cancer, liver cancer, and esophageal cancer, remain among the leading causes of cancer-related mortality worldwide. Despite substantial advances in targeted therapy, immunotherapy, antibody-drug conjugates, and precision oncology, therapeutic resistance continues to represent one of the greatest challenges limiting durable clinical responses and long-term patient survival. Increasing evidence suggests that resistance is not solely driven by genetic mutations, but also by dynamic molecular adaptation processes that enable tumor cells to survive under therapeutic pressure.

Recent studies have highlighted the critical roles of metabolic rewiring, epigenetic remodeling, tumor microenvironment interactions, immune evasion, stress-response signaling, and cellular plasticity in shaping therapy resistance across gastrointestinal cancers. In parallel, rapidly evolving technologies such as single-cell sequencing, spatial transcriptomics, organoid models, and multi-omic profiling are providing new opportunities to better understand resistance evolution and identify novel therapeutic vulnerabilities.

This Research Topic aims to provide a comprehensive platform for mechanistic, translational, and clinical studies investigating molecular adaptation mechanisms driving therapeutic resistance in gastrointestinal malignancies.

The goal of this Research Topic is to advance our understanding of how gastrointestinal tumors dynamically adapt to therapeutic pressure and develop resistance to current treatment strategies. We aim to highlight emerging mechanistic insights into metabolic adaptation, epigenetic regulation, immune remodeling, tumor microenvironment interactions, and signaling pathway reprogramming that collectively contribute to treatment failure and disease progression.

In addition to fundamental mechanistic studies, this Research Topic also seeks translational and clinically relevant investigations that identify predictive biomarkers, therapeutic vulnerabilities, and novel treatment strategies capable of overcoming resistance. By bringing together multidisciplinary perspectives, we hope to facilitate the development of more effective precision oncology approaches for gastrointestinal malignancies.

We welcome Original Research, Reviews, Mini Reviews, and Perspective articles related to molecular adaptation mechanisms and therapy resistance in gastrointestinal malignancies, including but not limited to:

● Molecular mechanisms underlying therapeutic resistance in gastrointestinal cancers
● Metabolic rewiring and redox adaptation during therapeutic stress
● Tumor microenvironment remodeling and immune escape mechanisms
● Epigenetic regulation, cellular plasticity, and signaling pathway reprogramming
● Resistance to immunotherapy, targeted therapy, chemotherapy, radiotherapy, and combination therapies
● Single-cell, spatial, organoid, and multi-omic approaches for resistance research
● Biomarker discovery and prediction of therapeutic response
● Novel therapeutic strategies targeting adaptive signaling networks in gastrointestinal malignancies
● Drug-tolerant persister (DTP) cells and senescence-like persister cells in gastric cancer, including their role in therapy resistance, tumor recurrence, and disease progression

Please note: Manuscripts consisting solely of bioinformatics, computational analysis, or predictions of public databases which are not accompanied by validation (independent clinical or patient cohort, or biological validation in vitro or in vivo, which are not based on public databases) are not suitable for publication in this journal.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

Articles that are accepted for publication by our external editors following rigorous peer review incur a publishing fee charged to Authors, institutions, or funders.

Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Case Report
• Clinical Trial
• Editorial
• FAIR² Data
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Systematic Review
• Technology and Code

Keywords: Gastrointestinal Cancers, Therapy Resistance, Molecular Adaptation, Cancer Metabolism, Translational Oncology, hepatocellular carcinoma; Metabolic dysfunction-associated fatty liver disease (MAFLD)

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.