Radiotherapy meets anticancer metallodrugs

Introduction

Chemoradiotherapy (CRT) is a cornerstone of modern cancer management, combining the systemic cytotoxicity of chemotherapy with the localized tumor control of radiotherapy (RT) [1]. RT exerts its therapeutic effect primarily by depositing ionizing energy within tissues, generating DNA damage directly and indirectly through reactive species [2]. Clinically, RT is used in over half of cancer patients and remains essential for both curative and palliative treatment [2]. In parallel, anticancer metallodrugs – most notably platinum (Pt) agents such as cisplatin and oxaliplatin – play indispensable roles in chemotherapy by inducing DNA crosslinking and apoptosis, forming the backbone of treatment for many solid malignancies [3]. Despite their clinical success, both modalities face significant limitations: RT efficacy is constrained by dose-limiting toxicity to surrounding normal tissues, while metallodrugs suffer from poor tumor selectivity, systemic toxicity, and resistance [1], 3]. These challenges highlight an unmet need for strategies that can spatially confine drug activity while preserving therapeutic potency (Figure 1).

Figure 1:

Radiotherapy is repurposed from a physical cytotoxic modality into a programmable chemical switch that activates, amplifies, or orchestrates metal-based cancer therapies with spatial precision. Radiopharmaceuticals lie at the intersection of radiotherapy and metallodrug therapy, and are emerging as key players in clinical cancer therapy. MOF: Metal-organic framework; ROS: Reactive oxygen species.

Concurrently, modern radiotherapy has undergone a technological transformation, enabling three-dimensional conformal targeting and highly localized dose deposition with minimal damage to surrounding tissues [2]. This evolution raises a critical question for contemporary oncology: can the precision of radiotherapy be chemically integrated with metal-based drugs, rather than merely combined at the regimen level? Addressing this question has led to a new conceptual framework in which radiation energy and metallodrug chemistry intersect, allowing metal systems to actively shape how radiotherapy is delivered, amplified, and biologically interpreted.

Upon irradiation, biological water undergoes radiolysis to generate hydrated electrons (e^-_aq), hydroxyl radicals (•OH), and hydrogen atoms (•H), creating a transient yet highly reactive chemical microenvironment confined to irradiated regions [4]. These species can selectively engage redox-active metal complexes, enabling normally inert prodrugs to remain pharmacologically silent during systemic circulation and become activated only at the tumor site. This concept directly addresses long-standing challenges in chemoradiotherapy by enhancing therapeutic indices and enabling precise multimodal integration. In the following sections, we discuss this emerging landscape across RT-activated Pt prodrugs, non-Pt metallodrugs, and metal-based radiosensitizers.

Radiotherapy-driven activation of anticancer Pt prodrugs

The foundation of radiotherapy-triggered metallotherapy was established by Fu et al., who demonstrated that X-ray irradiation generates e^-_aq capable of reducing inert Pt(IV) prodrugs into cytotoxic Pt(II) species selectively within tumors [5]. The spatiotemporal confinement of activation enhanced both tumor selectivity and therapeutic efficiency, while reducing systemic side effects commonly associated with conventional Pt-based therapy. To overcome the limitation of localized external irradiation, radiopharmaceutical-based strategies were developed to serve as internal radiation switches for Pt(IV) prodrugs, culminating in targeted radionuclide therapy approaches that enable Pt drug activation even in metastatic lesions [6], 7]. Together, these studies chart a clear evolution from externally triggered activation in primary tumors to systemically delivered, internally radiating switches capable of addressing disseminated disease.

Radiotherapy-activated non-Pt metallodrugs

Beyond Pt, diverse metal centers offer distinct redox, photophysical, and even nuclear properties that expand the scope of RT-driven activation. Ruan et al. developed a ruthenium-based nanoplatform that exploits nanosurface energy transfer between gold and ruthenium to activate Ru(III) prodrugs under X-ray irradiation, inducing immunogenic cell death (ICD) and synergizing with immune checkpoint blockade [8]. Copper-based systems further illustrate how RT can unlock unconventional cell death pathways. In a nanocapsule, X-ray irradiation triggers controlled Cu⁺ ion release, leading to mitochondrial protein aggregation and oxidative stress-driven tumor cell cuproptosis, thereby coupling RT with emerging metal-dependent cytotoxic mechanisms [9]. Notably, the concept of RT-triggered activation can extend beyond X-ray to alternative radiation sources. A recent gadolinium-based system harnesses neutron capture reactions to induce nucleodynamic therapy, where neutron irradiation triggers nuclear reactions within Gd-containing agents, amplifying local damage and potentiating antitumor immunity [10]. This work highlights how radiotherapy-driven metallotherapy can evolve from radiochemical activation toward radiation-nuclear-immune coupling, expanding its relevance across radiation modalities. Consistent with the immunogenic effects observed in these systems, emerging studies further suggest that radiotherapy and metallodrugs engage innate immune sensing pathways at the molecular level [11]. Radiation-induced DNA damage, together with metal-mediated ICD, promotes cytosolic DNA accumulation and activation of the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) axis, thereby triggering type I interferon signaling [11]. Such signaling enhances dendritic cell activation, T-cell priming, and pro-inflammatory reprogramming of tumor-associated myeloid cells, providing mechanistic insight into the growing concept of radio-metallo-immunotherapy.

Metal-based radiosensitizers: from hafnium oxide to metal-organic framework (MOF) architectures

In parallel with prodrug activation, metal-based materials have emerged as powerful radiosensitizers that enhance the local effects of RT. Hafnium oxide (HfO₂) nanoparticles exemplify this approach: their high atomic number enables efficient X-ray energy absorption, leading to increased reactive oxygen species (ROS) generation and amplified DNA damage within tumors [12]. Notably, HfO₂-based radiosensitizers have received regulatory approval in Europe, underscoring the translational potential of metal-enabled radiosensitization. More recently, Hf-based MOFs have introduced additional functionality by integrating high-Z nodes with porous, chemically programmable architectures [12]. These platforms combine efficient energy deposition with drug loading, ROS amplification, and immune modulation, positioning metal radiosensitizers as active participants rather than passive enhancers of RT [13], [14], [15].

Conclusion and perspective

Radiotherapy meeting anticancer metallodrugs marks a fundamental convergence between physical oncology and chemical medicine. Rather than treating radiotherapy and metallotherapy as parallel or sequential modalities, emerging strategies increasingly position metal-based systems as intrinsic components of radiation-based cancer treatment. From activatable Pt(IV) prodrugs and non-Pt metal complexes to high-Z radiosensitizers, metallodrugs now participate directly in how radiation energy is deposited, transformed, and translated into biological responses.

Radiometal-based drugs represent a particularly compelling intersection of these two fields. By integrating radiochemistry with metal coordination chemistry, radiometallodrugs represent a clinically emerging convergence of radiotherapy and metallotherapeutic approaches. As radiometal chemistry continues to advance, such systems are poised to play an increasingly central role in precision oncology.

Looking forward, progress will depend on expanding both metallodrug design and radiation paradigms, spanning external-beam radiotherapy, targeted radionuclide approaches, neutron capture reactions, and charged-particle irradiation. From a translational perspective, aligning metal pharmacokinetics with radiation delivery, dose distribution, and biological timing will be critical. As radiophysics, metal chemistry, and nuclear medicine further converge, radiotherapy may evolve into an integrated metallochemical platform for precise, adaptive, and durable cancer control.

Despite these advances, several limitations remain. Radiotherapy-activated metal prodrugs may still undergo premature reduction or off-target activation in circulation, compromising spatial selectivity. In addition, heterogeneous radiation dose distribution, limited tumor retention, and systemic metal-associated toxicity may restrict therapeutic windows. Addressing these challenges will require improved prodrug stability, tumor-targeted delivery strategies, and precise synchronization between drug pharmacokinetics and radiation scheduling. The development of stimuli-responsive carriers, ligand-directed targeting, and radiodosimetry-guided treatment planning may further enhance safety and efficacy.