Epigenetic alterations play central roles in chemoresistance by regulating gene expression, signaling pathways, and CSC properties, thereby significantly affecting tumor drug sensitivity. Epigenetic d

The gap

Consensus across the literature

Supporting evidence — 4 representative gaps

• Medicinal inorganic chemistry: New perspectives and targets for the periodic table (2020) · doi

  Platinum anticancer drug understanding is a dynamic one and as molecular and cancer biology linked to genomics unravel more and more the complexity of tumor cells, so too does our need to place the mechanism of action of drugs like cisplatin grow. This I have tried to demonstrate here by showing how our basic studies have led to an appreciation of new targets for platinum agents, differentiating firstly the classes of mononuclear and polynuclear platinums. The “GAG” interactome is seen as an exciting target for development of metal-based drugs and adds a new dimension to approaches to targeting GAGs. Attempts to modulate GAG function such as inhibitors of biosynthesis, GAG-binding peptides, and mimetics for enzyme inhibition represent a broad and exciting area for therapeutics. Yet, new alternative strategies to exploit glycans in general as targets for clin- ical use are needed as therapeutic intervention of glycan function itself remains an understudied area compared to approaches for DNA and pro- teins. Pursuing this avenue is an exciting one for inorganic chemists and will incentivize the study of the role of endogenous metals in the extracellular matrix, besides offering opportunities for design of coordination compounds as drugs and analytical probes. A full description of the action of any metal- containing drug should take into account these possible interactions. The summary here is intended to show metalloglycomics as a coherent, inclusive interdisciplinary field that opens new areas for bioinorganic chemistry, expanding its study to the third major class of biomolecules after proteins and DNA/RNA. ARTICLE IN PRESS

  Keywords: drugs exciting platinum drug action here targets metal approaches function area anticancer understanding dynamic molecular
• Epigenetic regulation in cancer chemoresistance and combined therapeutic strategies (2026) · doi

  Epigenetic alterations play central roles in chemoresistance by regulating gene expression, signaling pathways, and CSC properties, thereby significantly affecting tumor drug sensitivity. Epigenetic drugs targeting these mechanisms, including DNMTi, HDACi, and emerging BET protein or RNA-modifying enzyme inhibitors, have shown potential to reverse resistance and enhance chemotherapy efficacy in preclinical studies and early clinical trials (Suraweera et al., 2025; Sun et al., 2023). Notably, combination strategies with conventional chemotherapeutics can intervene at multiple resistance levels, providing new avenues to overcome tumor chemoresistance. Frontiers in Cell and Developmental Biology 06 frontiersin.org Jiang et al. 10.3389/fcell.2026.1814084 that evidence

  Keywords: epigenetic chemoresistance tumor resistance alterations play central roles regulating gene expression signaling pathways properties thereby
• Cisplatin resistance in oral squamous cell carcinoma: mechanisms, reversal strategies, and emerging technologies (2026) · doi

  this platinum agent Cisplatin remains a cornerstone in the treatment of OSCC, yet the clinical efficacy of is frequently compromised by the emergence of drug resistance. The present review synthesizes current evidence to demonstrate that cisplatin resistance is not attributable to a single cause, but rather constitutes a complex, adaptive system. This system arises from the interplay between tumor cell-intrinsic alterations and extrinsic microenvironmental factors (Cheng et al., 2021), encompassing multiple interconnected dimensions such as genetic and epigenetic reprogramming, metabolic remodeling, evasion of regulated cell death, acquisition of stem-like properties, and dysregulation of the immune landscape. To address this multifaceted challenge, the research paradigm is shifting from purely mechanistic dissection toward the development of multi-target and multimodal intervention strategies. These strategies include the design of specific inhibitors against key resistance nodes, the use of nanotechnology for targeted drug delivery (Morgovan et al., 2025), the combination of cisplatin with immunotherapy to remodel the immunosuppressive microenvironment (Shibata et al., 2025), the exploitation of tumor-specific metabolic vulnerabilities (Zou et al., 2025). Collectively, such approaches represent an integrated therapeutic network targeting resistance across molecular, cellular, and microenvironmental scales. Ultimately, overcoming cisplatin resistance requires a fundamental evolution in therapeutic approach, driven by emerging technologies. Patient-derived organoids offer a physiologically relevant platform for in vitro drug testing and personalized strategy validation (Um et al., 2025). Single-cell multi-omics technologies decode tumor heterogeneity at un preceden ted resolu tion, p in point ing r are resist ant subpopulations and the crosstalk of these populations with the microenvironment (Doerfler et al., 2025). Artificial intelligence and machine learning integrate vast multi-scale datasets to build predictive models and accelerate biomarker and drug discovery (Liu et al., 2025). The synergy of these technologies—where single- cell analysis provides high-resolution maps, organoids enable functional testing (Han et al., 2025), and AI facilitates data integration and optimization—is propelling the field from population-level observations toward precision interventions guided by cellular atlases and individualized models. In summary, advancing against cisplatin resistance in OSCC necessitates a cohesive framework that links systematic mechanistic understanding, innovative therapeutic strategies, and cutting-edge translational technologies. Future efforts must focus on deepening systems-level comprehension of resistance dynamics and accelerating the clinical integration of organoid models, single-cell technologies, Given the broad and integrative scope of this narrative review, we conducted a comprehensive literature search to synthesize the mult

  Keywords: resistance cisplatin cell technologies drug single tumor multi strategies therapeutic models oscc clinical review system
• Metabolic reprogramming and plasticity of cancer stem cells (2026) · doi

  Anti-CSCs therapies poses a promising strategy in oncology due to their role in tumor initiation, therapy resistance, metastasis, and recurrence. Conventional treatments such as chemotherapy and radiotherapy primarily eliminate rapidly proliferating tumor cells but often fail to eliminate CSCs, especially the CSCs remaining in a quiescent state. As a result, surviving CSCs can repopulate the tumor after therapy (Stouras et al., 2023). Actually, there is no therapeutic tool that can find, identify and eliminate specifically CSCs, thus anti-CSCs strategies may target the stemness-, EMT- and metabolic plasticity-related signaling pathways (Milella et al., 2025). However, the features that characterize CSCs are also those that enable them to efficiently avoid current therapeutic tools. Heterogeneity and plasticity causes that the CSCs population is not homogeneous; different CSCs at the same tumor exhibit various gene expression profiles, metabolic interactions, and responses to therapy, making up overall tumor heterogeneity and therapy resistance. At the same tumor site, CSCs can synthetize various drug efflux transporters, DNA repair enzymes, and anti-apoptotic proteins, allowing them to survive anticancer therapy (Heppner et al., 1978). Another major challenge in anti-CSCs therapy is the metabolic of CSCs. Their metabolic plasticity allows them to survive under hostile conditions, evade metabolic inhibition and therapy-induced cell death. A key component of this flexibility is the capacity of CSCs to reprogram ATP production in response to metabolic targeting. To enable CSCs-targeted therapy, specific biomarkers are necessary, what remains a significant challenge for both CSCs research and therapeutic targeting. Several markers, including CD44, CD133, ALDH1 and EpCAM, have been widely used to detect and isolate CSCs populations across different cancer types. However, these markers are not universally expressed and are frequently shared with non-CSCs, raising concerns about their specificity and potential off-target effects (Lee et al., 2025a). The crucial therapeutic the process of CSCs target phenotypic change. target to is 6.1 Stem cells signaling pathways inhibitors and differentiation, survival. These One of the most frequently studied strategies is the inhibition of key signaling pathways responsible for maintaining CSCs stemness, especially embryonic stem cells markers, such as OCT-4, Nanog, Notch, and Wnt/β-catenin. These pathways regulate CSCs self- renewal, strategies demonstrate high in vitro efficacy, but have no clinical translation (Lee et al., 2025a). During research of stem-like properties in lung cancer cells, Chen et al. (2008) revealed that knock-down of OCT-4 expr

  Keywords: cscs therapy tumor metabolic anti cells therapeutic target pathways eliminate strategies plasticity signaling them markers