Targeting the Enhanced Sensitivity of Radiotherapy in Cancer: Mechanisms, Applications, and Challenges

Abstract

Cancer is a major public health, societal, and economic challenge worldwide. According to Global Cancer Statistics 2022, it is estimated that by 2050, there will be 35 million new cancer cases globally. Although patient survival rates have improved through various therapeutic approaches, including surgery, chemotherapy, and radiotherapy, treatment efficacy remains limited once tumor metastasis occurs. Among various cancer treatment strategies, radiotherapy plays a crucial role. Along with surgery and chemotherapy, radiotherapy is a cost-effective single-modality treatment, accounting for approximately 5% of total cancer care costs. The use of radiosensitizing agents such as histone deacetylase inhibitors, 2-deoxy-d-glucose, enterolactone, and squalene epoxidase can enhance radiotherapy effectiveness. Recent radiosensitization methods involve physical stimuli and chemical radiosensitizers. However, improving their efficacy, durability, and overcoming radioresistance remain significant challenges. This review first introduces current applications of radiotherapy in cancer treatment, the molecular mechanisms underlying its anticancer effects, and its side effects. Second, it discusses the main types of radiosensitizers, their latest applications, and recent challenges in cancer treatment. Finally, it emphasizes on clinical trials of radiosensitizing agents and explores potential biomarkers for radiotherapy response in cancer. Multifunctional nanoparticles have shown greater clinical applicability than single-functional nanoparticles. Future research will focus on enhancing the drug-carrying capacity of nanomaterials to further improve radiotherapy outcomes.

Keywords: combination therapy; radiosensitization; radiosensitizers; radiotherapy.

FIGURE 1

DNA damage repair. SSB is repaired by the BER, NER, and MMR machineries. DSB is repaired by HRR and NHEJ. Abbreviations: SSB, single strand break; DSB, double strands break; MMR, mismatch repair; NER, nucleotide excision repair; BER, base excision repair; HRR, homologous recombination repair; NHEJ, nonhomologous end joining.

FIGURE 2

The important molecular mechanisms and signaling pathways of the sensitivity and resistance of radiotherapy in cancer. In the review, we mainly summarized four mechanisms including DNA damage repair, apoptosis, autophagy, mitochondrial respiration, and tumor microenvironment. Reproduced with permission from Ref. [9], © Published by Elsevier Ltd. 2022. Ref. [49], CC BY 4.0 no copyright need. Ref. [78], © Published by Elsevier Ltd. 2021. Ref. [83] © Published by Elsevier Ltd. 2019.

FIGURE 3

The clinical progress of drugs to affect sensitivity of radiotherapy in cancer. The clinical agents including HDAC inhibitors, natural compounds, and other chemical and molecular agents of enhanced sensitivity of radiotherapy in cancer.

FIGURE 4

The clinical progress of nanomaterials in radiotherapy. The developing and optimizing various types of metal‐based nanoparticles for radiation‐enhancing purposes in cancer.

FIGURE 5

The main damaged organs suffered from radiotherapy. Besides the heart effect, pneumonitis, and pulmonary fibrosis, radiotherapy‐induced fatigue, osteoporosis, and progressive hyalinization and fibrosis of medullary spaces are also observed in breast cancer patients undergoing radiotherapy. In addition, the other side effects can be observed in the skin, ovary, and uteri. This figure was created using BioRender.