Drug resistance in solid tumors remains a major obstacle in oncology, frequently leading to treatment failure and disease relapse. A central contributor to this resistance is metabolic reprogramming, wherein tumor cells adapt to therapeutic pressure by altering key pathways such as glycolysis, oxidative phosphorylation, and lipid metabolism. These metabolic shifts enhance tumor cell plasticity, facilitating escape from chemotherapy, targeted agents, and immunotherapies.

At the molecular level, resistance arises through a complex interplay of genetic mutations, epigenetic alterations, efflux pump activation, and pro-survival signaling cascades. The tumor microenvironment (TME) further exacerbates resistance by creating protective niches shaped by hypoxia, acidic pH, and stromal interactions that impair drug penetration and efficacy.

To overcome these challenges, emerging strategies include combination regimens, metabolic pathway inhibitors, and agents that modulate the TME. A deeper understanding of these interconnected resistance mechanisms is critical to advancing more effective and durable cancer therapies.

This special issue invites original research and reviews that explore the molecular underpinnings of drug resistance in solid tumors, with particular emphasis on metabolic reprogramming, tumor microenvironmental influences, and innovative therapeutic strategies. We aim to highlight the complex biological and molecular processes that enable tumor cells to evade treatment, including alterations in energy metabolism, genetic and epigenetic changes, and the role of stromal and immune components within the tumor microenvironment. By showcasing interdisciplinary approaches-from molecular biology to translational oncology- this issue seeks to foster novel insights that can inform the development of more effective, personalized treatment regimens. Additionally, we encourage submissions that explore emerging therapeutic interventions, including metabolic inhibitors, Immunotherapeutics, and rational drug combinations. Ultimately, this special issue aspires to serve as a comprehensive resource for researchers and clinicians working to overcome therapeutic resistance and improve outcomes for patients with solid tumors.

This special issue focuses on the complex and evolving landscape of drug resistance in solid tumors, with particular emphasis on the interplay between metabolic reprogramming, the tumor microenvironment, and resistance-associated molecular pathways. We welcome original research articles, reviews, and short communications that provide new insights into the metabolic adaptations of cancer cells under therapeutic stress, the genetic and epigenetic drivers of resistance, and the role of stromal and immune components in shielding tumors from treatment.

Topics of interest include, but are not limited to:

• Mechanisms of metabolic reprogramming in drug-resistant tumors

• Tumor microenvironment-mediated therapy resistance

• Novel metabolic or immunotherapeutic interventions

• Biomarker discovery and precision medicine approaches

• Resistance to targeted therapy, chemotherapy, or immunotherapy

• Preclinical and clinical studies addressing therapeutic resistance

Authors are invited to submit high-quality original research articles, comprehensive reviews, or short communications relevant to the scope of this special issue. All submissions will undergo a rigorous peer-review process to ensure scientific integrity and relevance. Manuscripts should be prepared according to the journal’s submission guidelines, including formatting, referencing, and ethical standards.

Please note that manuscripts consisting solely of bioinformatics or computational analysis of public omics databases that are not supplemented by relevant functional validation (clinical cohort or biological validation in vitro or in vivo) are out of scope for this Research Topic.

For inquiries regarding suitability or scope, please contact the Guest Editors at: saleemmr@ucmail.uc.edu

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Navigating Drug Resistance in Solid Tumors: Biomarkers, Metabolism, and Immune-Based Therapies