Platinum‐Based Chemotherapeutics in the Modern Era: From Classical DNA ‐Targeting Mechanisms to Next‐Generation Innovations in Cancer Therapy

ABSTRACT Thanks to their DNA‐crosslinking methods, platinum‐based chemotherapeutics—which were first introduced by the coincidental discovery of cisplatin in 1965—have long been a mainstay of cancer treatment, with notable effectiveness in treating colorectal, ovarian, and testicular cancers. In order to address the enduring problems of toxicity, resistance, and restricted selectivity, this study charts their development from the traditional agents cisplatin, carboplatin, and oxaliplatin to next‐generation developments. Classical mechanisms, rooted in aquation and apoptotic induction, are now complemented by emerging targets, including RNA, mitochondria, and protein–protein interactions, alongside novel cell death pathways like ferroptosis. Nonclassical complexes, such as Pt(IV) prodrugs and multinuclear agents, enhance delivery and overcome resistance, while synergistic strategies with immunotherapy (e.g., PD‐1 inhibitors), nanoparticle delivery, and radiotherapy amplify efficacy. Precision medicine advances patient stratification via genomic (e.g., TP53 and BRCA) and proteomic biomarkers, liquid biopsies for real‐time monitoring, and pharmacogenomics to adapt dosing. Sustainability initiatives, stable formulations, affordable generics, and green synthesis guarantee worldwide access, especially in low‐resource environments. Recent trials have validated the use of hypoxia‐activated prodrugs, AI‐driven predictive models, and DNA repair inhibitors (e.g., NER and PARP) in the fight against resistance. Looking forward, integration with CRISPR, 3D tumor modeling, and epigenetic targeting heralds a new frontier, supported by interdisciplinary collaboration bridging chemistry, biology, and technology. This convergence of foundational principles and cutting‐edge innovations positions platinum therapy for a transformative era, promising enhanced precision, efficacy, and equity in cancer care worldwide.