Molecular Mechanisms of Cancer Resistance to Therapy

Despite major advances in targeted therapies, immunotherapies, and combination regimens, therapy resistance remains a central barrier to durable cancer control. Tumors frequently evade treatment through a range of molecular and cellular adaptations, leading to residual disease, relapse, and metastasis. Resistance may be intrinsic (pre-existing) or acquired (evolving under therapeutic pressure), and it often reflects the interaction of tumor cell–autonomous programs with the surrounding tumor microenvironment, systemic factors, and treatment-driven selection. A clearer understanding of these mechanisms is essential for identifying actionable vulnerabilities and for designing strategies to prevent, delay, or overcome resistance.This Research Topic aims to bring together cutting-edge studies that elucidate the molecular mechanisms underlying resistance to cancer therapy across tumor types and therapeutic modalities. We welcome contributions that investigate how cancers rewire signaling networks and regulatory circuits to withstand treatment, including but not limited to: genomic alterations (mutations, copy number changes, structural variants), epigenetic remodeling, transcriptional and translational reprogramming, adaptive pathway compensation, and post-translational modifications that alter drug response. Particular interests include mechanisms governing DNA damage repair and replication stress responses, apoptosis and other regulated cell death pathways, cell cycle control, metabolic plasticity, stress response programs, and phenotypic state transitions such as epithelial–mesenchymal plasticity, lineage switching, and stem-like persistence.Resistance is also shaped by tumor heterogeneity and evolution, including clonal selection, subclonal cooperation, and the emergence of drug-tolerant persister populations. Submissions exploring evolutionary dynamics, spatial biology, and the role of microenvironmental cues—such as hypoxia, inflammation, stromal remodeling, and immune-mediated selection—are encouraged. We also welcome work that links resistance mechanisms to biomarkers of response and relapse, including liquid biopsy approaches and longitudinal sampling, as well as studies that leverage functional genomics, single-cell and multi-omics profiling, organoids, patient-derived models, or advanced in vivo systems.The scope includes resistance to targeted agents, cytotoxic chemotherapy, radiotherapy, endocrine therapy, and immunotherapy, as well as combination strategies designed to counter resistance (e.g., synthetic lethal approaches, adaptive dosing, rational co-targeting, or microenvironment-focused interventions). Both original research and thoughtfully constructed reviews/meta-analyses are invited. By integrating mechanistic insights with translational relevance, this Research Topic seeks to accelerate the development of next-generation therapeutic strategies that deliver more durable responses for patients.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. Topic editors: Nimrat Chatterjee, Sanja Aveic, Remi Adelaiye-Ogala Source: https://www.frontiersin.org/research-topics/78922/molecular-mechanisms-of-cancer-resistance-to-therapy