Innovative Delivery Strategies and Drug Repurposing to Overcome Treatment Resistance in Cancer

Treatment resistance remains a central limitation in the pharmacological management of aggressive malignancies, including pancreatic cancer, glioblastoma, triple-negative breast cancer, and metastatic melanoma. Despite advances in anticancer drug development, tumor heterogeneity, adaptive signaling networks, drug efflux mechanisms, and tumor microenvironment–mediated protection frequently compromise therapeutic efficacy. Contemporary cancer pharmacology increasingly focuses on overcoming these barriers through rational drug design, improved delivery systems, and combination strategies. In particular, nanoscale drug delivery platforms have demonstrated potential to enhance tumor selectivity and bioavailability of anticancer agents. Parallel advances in mechanistic oncology have identified key pathways involved in resistance evolution, enabling new opportunities for pharmacological intervention. Furthermore, drug repurposing and the use of bioactive small molecules with defined molecular targets are emerging as efficient strategies to accelerate therapeutic innovation and improve clinical response in refractory cancers.This Research Topic aims to advance the pharmacological understanding and therapeutic innovation required to overcome drug resistance in aggressive malignancies. A major challenge in oncology remains the multifactorial nature of resistance, driven by genetic alterations, epigenetic reprogramming, tumor microenvironmental adaptation, and altered drug transport dynamics. Recent developments in nanomedicine have enabled the design of tumor-targeted and stimuli-responsive delivery systems that improve drug accumulation, enhance intracellular uptake, and reduce systemic toxicity. In parallel, drug repurposing strategies are gaining traction as cost-effective and rapid approaches to identify new anticancer applications for clinically approved agents. Additionally, increasing attention is being directed toward bioactive small molecules, including structurally defined compounds of natural origin, that exhibit mechanistically validated roles in modulating drug response pathways such as apoptosis, autophagy, and oxidative stress regulation. By integrating mechanistic pharmacology, advanced delivery technologies, and translational drug development approaches, this Research Topic seeks to highlight strategies that effectively bypass resistance mechanisms and improve the efficacy of existing and emerging anticancer therapies.This article collection welcomes submissions addressing pharmacological and translational strategies to overcome resistance in cancer therapy. We encourage studies focusing on nanotechnology-based drug delivery systems, including targeted, multifunctional, and stimuli-responsive platforms designed to enhance tumor specificity and therapeutic efficacy of anticancer drugs. Contributions on drug repurposing supported by mechanistic, preclinical, or early clinical evidence are highly encouraged.We also welcome studies investigating bioactive small molecules with defined molecular mechanisms of action, including structurally characterized compounds derived from natural sources that demonstrate pharmacological modulation of drug resistance pathways. Mechanistic studies elucidating tumor microenvironment interactions, efflux transporters, signaling rewiring, and cell death regulation are particularly relevant. Submissions should emphasize pharmacological rigor, including multi-model validation (multiple cancer cell lines and/or in vivo systems), drug selectivity, and, where applicable, formulation stability and translational relevance. We welcome Original Research, Review, Mini Review, and Perspective articles.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 Research Topic.The Topic Editors did not declare any conflict of interests. Topic editors: Zeeshan Ahmad Bhutta, Kyung-Chul Choi, Dr. Md. F. Kulyar Source: https://www.frontiersin.org/research-topics/81806/innovative-delivery-strategies-and-drug-repurposing-to-overcome-treatment-resistance-in-cancer