The improvement of diagnostic techniques and the efficacy of new therapies in clinical practice have allowed cancer patients to reach a higher chance to be cured together with a better quality of life. However, tumors still represent the second leading cause of death worldwide. On the contrary, chemotherapy and radiotherapy (RT) still lack treatment plans which take into account the biological features of tumors and depend on this for their response to treatment. Tumor cells’ response to RT is strictly-connected to their radiosensitivity, namely, their ability to resist and to overcome cell damage induced by ionizing radiation (IR). For this reason, radiobiological research is focusing on the ability of chemical compounds to radiosensitize cancer cells so to make them more responsive to IR. In recent years, the interests of researchers have been focused on natural compounds that show antitumoral effects with limited collateral issues. Moreover, nutraceuticals are easy to recover and are thus less expensive. On these bases, several scientific projects have aimed to test also their ability to induce tumor radiosensitization both in vitro and in vivo. The goal of this review is to describe what is known about the role of nutraceuticals in radiotherapy, their use and their potential application.

The hypoxic pattern of glioblastoma (GBM) is known to be a primary cause of radioresistance. Our study explored the possibility of using gene knockdown of key factors involved in the molecular response to hypoxia, to overcome GBM radioresistance. We used the U87 cell line subjected to chemical hypoxia generated by CoCl2 and exposed to 2 Gy of X-rays, as single or combined treatments, and evaluated gene expression changes of biomarkers involved in the Warburg effect, cell cycle control, and survival to identify the best molecular targets to be knocked-down, among those directly activated by the HIF-1α transcription factor. By this approach, glut-3 and pdk-1 genes were chosen, and the effects of their morpholino-induced gene silencing were evaluated by exploring the proliferative rates and the molecular modifications of the above-mentioned biomarkers. We found that, after combined treatments, glut-3 gene knockdown induced a greater decrease in cell proliferation, compared to pdk-1 gene knockdown and strong upregulation of glut-1 and ldha, as a sign of cell response to restore the anaerobic glycolysis pathway. Overall, glut-3 gene knockdown offered a better chance of controlling the anaerobic use of pyruvate and a better proliferation rate reduction, suggesting it is a suitable silencing target to overcome radioresistance.

Modern oncology increasingly relies on personalized strategies that aim to customize medical interventions, using both tumor biology and clinical features to enhance efficacy and minimize adverse effects. In recent years, precision medicine has been implemented as part of systemic therapies; however, its integration into radiation therapy (RT) is still a work in progress. Conventional RT treatment plans are based on the Linear Quadratic (LQ) model and utilize standardized alpha and beta ratios (α/β), which ignore the high variability in terms of treatment response between and within patients. Recent advances in radiobiology, as well as general medical technologies, have also driven a shift toward more tailored approaches, including in RT. This review provides an overview of current knowledge and future perspectives for the personalization of RT, highlighting the role of tumor and patient-specific biomarkers, advanced imaging techniques, and novel therapeutic approaches. As an alternative to conventional RT modalities, hadron therapy and Flash RT are discussed as innovative approaches with the potential to improve tumor targeting while sparing normal tissues. Furthermore, the synergistic combination of RT with immunotherapy is discussed as a potential strategy to support antitumor immune responses and overcome resistance. By integrating biological insights, technological innovation, and clinical expertise, personalized radiation therapy may significantly advance the precision oncology paradigm.

Radiomics provides a structured approach to support clinical decision-making through key steps; however, users often face difficulties when switching between various software platforms to complete the workflow. To streamline this process, matRadiomics integrates the entire radiomics workflow within a single platform. This study extends matRadiomics to preclinical settings and validates it through a case study focused on early malformation differentiation in a zebrafish model. The proposed plugin incorporates Pyradiomics and streamlines feature extraction, selection, and classification using machine learning models (linear discriminant analysis—LDA; k-nearest neighbors—KNNs; and support vector machines—SVMs) with k-fold cross-validation for model validation. Classifier performances are evaluated using area under the ROC curve (AUC) and accuracy. The case study indicated the criticality of the long time required to extract features from preclinical images, generally of higher resolution than clinical images. To address this, a feature analysis was conducted to optimize settings, reducing extraction time while maintaining similarity to the original features. As a result, SVM exhibited the best performance for early malformation differentiation in zebrafish (AUC = 0.723; accuracy of 0.72). This case study underscores the plugin’s versatility and effectiveness in early biological outcome prediction, emphasizing its applicability across biomedical research fields.

Objectives: To investigate how the FLASH effect modulates radiation response on multiple developmental endpoints of zebrafish embryos under normoxic and hypoxic conditions, after irradiation with proton beams at a conventional and an ultra-high dose rate (UHDR). Methods: Embryos were obtained from adult zebrafish and irradiated with a 228 MeV proton beam 24 h post-fertilization (hpf) at a dose rate of 0.6 and 317 Gy/s. For the hypoxic group, samples were kept inside a hypoxic chamber prior to irradiation, while standard incubation was adopted for the normoxic group. After irradiation, images of single embryos were acquired, and radiation effects on larval length, yolk absorption, pericardial edema, head size, eye size, and spinal curvature were assessed at specific time points. Results: Data indicate a general trend of significantly reduced toxicity after exposure to a UHDR compared to conventional regimes, which is maintained under both normoxic and hypoxic conditions. Differences are significant for the levels of pericardial edema induced by a UHDR versus conventional irradiation in normoxic conditions, and for eye and head size in hypoxic conditions. The toxicity scoring analysis shows a tendency toward a protective effect of the UHDR, which appears to be associated with a lower percentage of embryos in the high score categories. Conclusions: A radioprotective effect at a UHDR is observed both for normoxic (pericardial edema) and hypoxic (head and eye size) conditions. These results suggest that while the UHDR may preserve a potential to reduce radiation-induced damage, its protective effects are endpoint-dependent; the role of oxygenation might also be dependent on the tissue involved.

Radiation modifiers are largely studied for their contribution to enlarging the treatment window. Curcumin is already known for its antioxidant properties; however, its role as a radioprotector in preclinical studies is affected by the well-known low absorption and bioavailability of curcumin. In this study, curcumin’s radioprotection ability has been evaluated in zebrafish larvae, by taking advantage of quantifying curcumin absorption and evaluating its fluorescence in transparent embryos. A curcumin range of 1–10 μM was tested to select the non-toxic concentrations to be used for a pre-treatment of photon beam irradiation using a 2–15 Gy range of doses. The post-treatment analysis within 120 h post-fertilization (hpf) included an assessment of mortality and malformation rates and behavioral and gene expression analysis. A total of 2.5 and 5 μM of curcumin pre-treatment showed a radioprotective role, significantly reducing the frequency of embryo malformations and damaged entities. This sparing effect disappeared using 15 Gy, showing the radiation effect’s prevalence. Gene expression analysis reconducted this radioprotective ability for antioxidant gene network activation. The curcumin-induced activation of the antioxidant gene network promoted radioprotection in zebrafish.