Neural regulation of cancer therapy resistance is established unevenly across tumor types, signal sources, and treatments. This review proposes an evidence-calibrated framework that evaluates each candidate mechanism through its source, signal or activity pattern, receptor, target cell, and treatment context. We organize candidate neural contributions into four author-defined, overlapping analytical programs: survival and damage tolerance; cell-state plasticity and drug-tolerant persistence; neuroimmune suppression; and metabolic, vascular, and stromal adaptation. These categories facilitate comparison rather than denote equally established mechanisms: survival and selected neuroimmune routes have more direct treatment-linked support than many vascular and stromal hypotheses. Local innervation is distinguished from systemic neuroendocrine signaling and non-neuronal ligand production, while circuit integration in brain tumors is separated from predominantly paracrine and perineural interactions in peripheral cancers. An explicit hierarchy differentiates prospective biomarker-supported clinical benefit (Level 1), early interventional pharmacodynamic evidence (Level 2), treatment-specific preclinical intervention evidence (Level 3), and association (Level 4). Source resolution and rescue are assessed separately within each study. Therapy-associated sprouting, receptor adaptation, and cancer-induced nerve injury are evaluated as distinct processes; current evidence does not establish treatment-induced neural rewiring as a universal resistance driver. Study-level comparisons, model-selection criteria, and operational biomarker examples identify where neural targeting is supported, where only pathway-level dependence is demonstrated, and where additional causal validation is required. The framework is intended to improve selection and interpretation of mechanism-matched combinations, rather than infer oncologic efficacy from the availability of neuromodulatory drugs.

Antimicrobial peptides offer rapid, often membrane centered activity, but their therapeutic translation is limited by proteolytic instability, toxicity, reduced activity under physiological conditions, unfavourable pharmacokinetics, and manufacturing challenges. Peptidomimetics seek to retain the functional logic of antimicrobial peptides while improving these properties. This review presents a unified framework for peptidomimetic based antimicrobial discovery. It describes the fundamentals and classes of antimicrobial peptidomimetics, discusses mechanisms of antibacterial activity and the molecular basis of multidrug resistance. The review also highlights advances in molecular modelling and the growing role of artificial intelligence. A literature search was performed using PubMed, Scopus, Web of Science, and Google Scholar to review experimental, computational, and translational studies on peptidomimetics. Relevant studies were selected. The review examines the fundamentals of peptidomimetics, including key classes, structural modifications, and optimization strategies designed to overcome antimicrobial resistance. The review also highlights that effective antibacterial action involves electrostatic accumulation, selective membrane anchoring, transition into a membrane active conformation, and, in some cases, permeation to intracellular targets. In Gram-negative organisms, lipopolysaccharide organization and Ca[2+]/Mg[2+] mediated cross linking increases the energetic barrier to membrane engagement. Furthermore, advances in synthetic methodologies, coupled with AI, are expected to enable faster and more efficient synthesis routes. Peptidomimetics seek to redefine antibacterial strategy by encoding resistance resilience into molecular design rather than relying on single target novelty. Their future impact will depend on integrating structure-activity relationships, mechanistic understanding with AI guided design.

P-glycoprotein (P-gp, also known as ABCB1) is a member of the ATP-binding cassette (ABC) transporter family that protects tissues from diverse xenobiotics and contributes to multidrug resistance in cancer. Despite extensive structural, biochemical, and biophysical studies, the molecular basis of its remarkable substrate polyspecificity remains incompletely understood. Recent structures of P-gp and its homologs, including zebrafish Abcb4, have revealed extensive conformational heterogeneity and provided unprecedented views of substrate and inhibitor recognition. In this review, we integrate structural and functional studies to examine how conformational variability of the drug-binding site contributes to P-gp polyspecificity. We highlight the continuum of inward-facing conformations and the coupling between local changes in drug-binding site architecture, including transmembrane-helix rotation and tilting, and the global opening and closing of the transporter's two pseudo-symmetric halves. We propose a dynamic conformational sampling model in which diverse substrates can recognize and possibly stabilize different conformational states of P-gp and, in some cases, adopt distinct binding poses. We further discuss how this dynamic view provides a framework for understanding the complex pharmacological behavior of P-gp and may inform the development of more effective inhibitors.

Triple-negative breast cancer (TNBC) lacks actionable therapeutic targets and remains highly dependent on cytotoxic chemotherapy, yet the rapid emergence of cisplatin resistance severely limits clinical benefits. The molecular mechanisms underlying this resistance and effective combination strategies remain incompletely defined. Here, we identify an epigenetic-metabolic signaling axis that drives cisplatin resistance in TNBC. Mechanistically, the histone demethylase KDM5A suppresses the endogenous protein kinase A inhibitor PKIA, thereby activating the cAMP-PKA pathway, enhancing CREB phosphorylation, and upregulating mitochondrial deacetylase SIRT3 transcription. Elevated SIRT3 subsequently deacetylates and activates SOD2, reducing intracellular reactive oxygen species (ROS) levels and attenuating cisplatin-induced oxidative damage and apoptosis, thereby promoting a drug-resistant phenotype. Upstream, we demonstrate that the E3 ubiquitin ligase UBR5 directly interacts with KDM5A and mediates its ubiquitin-dependent degradation, acting as a negative regulator of this pathway. Loss or attenuation of UBR5 stabilizes KDM5A and amplifies the KDM5A-cAMP-PKA-SIRT3 signaling cascade, conferring resistance to cisplatin. Therapeutically, pharmacologic inhibition of KDM5A restores cisplatin sensitivity and suppresses tumor growth in both cellular and in vivo models. Collectively, our findings establish the UBR5-KDM5A-cAMP-PKA-SIRT3 axis as a central regulator of cisplatin resistance in TNBC and highlight KDM5A as a promising therapeutic target for combination treatment strategies.

Chemoresistance is a principal cause of treatment failure in bladder cancer (BLCA), yet the mechanisms that actively maintain resistance remain poorly defined. Gemcitabine (GEM) resistance is classically attributed to impaired drug uptake via human equilibrative nucleoside transporter 1 (hENT1) and activation of pro-survival cell signaling pathways. However, these mechanisms do not explain how resistance is stably sustained over time. Here we uncover an autophagy-dependent pathway that maintains GEM chemoresistance, in which nucleolin (NCL) shields the RNA-binding protein polypyrimidine tract-binding protein 1 (PTBP1) from microtubule-associated protein 1 light chain 3 beta (LC3B)-mediated autophagic degradation. Consequently, NCL-mediated stabilization of PTBP1 maintains glycolytic reprogramming in GEM-resistant BLCA cells, whereas NCL additionally promotes anti-apoptotic signaling. Notably, PTBP1 is enriched and preserved as a functional and surface-accessible dependency through NCL-mediated evasion of autophagic degradation. To exploit this vulnerability, we developed a monovalent dual-target DNA aptamer, SWL-3, that undergoes preferential internalization through surface-accessible PTBP1 while also binding NCL, enabling selective recognition of xenograft tumors in vivo and clinical BLCA specimens in vitro. By bypassing classical hENT1-dependent drug uptake, site-specifically conjugated SWL-3G achieves efficient intracellular drug accumulation and selectively reduces the viability of GEM-resistant, PTBP1-enriched cells. Together, these findings reveal NCL-mediated protein shielding from autophagic degradation as a mechanism that sustains GEM resistance and establish these resistance-maintaining dependencies as actionable targets for precision therapy in refractory disease.

Drug resistance remains a major challenge to successful cancer treatment. Although cell-autonomous genetic, molecular, and cellular modifications have historically been linked to resistance, there is growing evidence that extracellular vesicles (EVs) can promote the intercellular transfer of resistance-associated components. With a focus on the ways in which EV cargo modifies treatment response, this review critically investigates the role of EVs in therapeutic resistance in breast cancer, lung cancer, leukemia, glioblastoma, pancreatic cancer, and melanoma. The effects of major EV-associated factors on drug efflux, apoptosis, survival signaling, DNA repair, and metabolic adaptation are discussed. These factors include drug-efflux transporters, anti-apoptotic and oncogenic proteins, non-coding RNAs, DNA-repair molecules, metabolic components, and drug-sequestering molecules. As components of the tumor microenvironment that may strengthen treatment resistance, the review also considers EVs released by mesenchymal stromal cells, cancer-associated fibroblasts, and tumor-associated macrophages. By combining these results, we present a community-level view of EV-mediated resistance, where multidrug resistance and treatment failure may be caused by tumor-intrinsic resistance, horizontal transfer via tumor-derived EVs, and TME-derived EV signaling. Lastly, the potential of EVs as delivery systems, biomarkers, predictors, and therapeutic targets is examined, along with the present translational constraints and open issues. This synthesis emphasizes EV-mediated communication as a crucial addition to traditional cancer medication resistance models.

Resistance to tyrosine kinase inhibitors (TKIs), particularly pazopanib, is the primary driver of treatment failure in patients with advanced clear cell renal cell carcinoma (ccRCC). However, the epitranscriptomic mechanisms underlying TKI resistance, especially the regulatory role of N6-methyladenosine (m[6]A) modification, remain poorly understood. We integrated multi-omics analyses with in vitro and in vivo functional assays, multi-cohort clinical validation, and development of targeted small-molecule inhibitors to dissect the role of methyltransferase-like 16 (METTL16) in ccRCC resistance to pazopanib. METTL16, an independent catalytically active m[6]A writer, was significantly upregulated in pazopanib-resistant ccRCC cells and in clinical tumor tissues. High METTL16 expression was strongly associated with advanced nuclear grade, pazopanib non-response, and unfavorable clinical prognosis in ccRCC patients. Functionally, METTL16 promoted ccRCC proliferation, metastasis, stemness, and pazopanib resistance in both in vitro and in vivo settings. Mechanistically, METTL16 bound and stabilized the small nucleolar RNA SNORA80B in an m[6]A-dependent manner, which was associated with enhanced translational output and activation of the JAG1/Notch signaling axis. A novel small-molecule inhibitor targeting the METTL16 methyltransferase activity pocket, METTL16-IN, markedly suppressed resistant tumor growth and synergized with pazopanib to reverse TKI resistance. Our findings support a model in which METTL16-mediated m[6]A remodeling contributes to pazopanib resistance through altered ribosome biogenesis and translational reprogramming.