BASIC PRINCIPLES OF PROTON THERAPY

Physical characteristics of proton therapy

Radiation therapy, an important cancer treatment strategy, is primarily classified into photon and particle therapies based on the type of radiation used. Proton therapy is a form of particle therapy that uses protons instead of conventional photons. 11 The fundamental principle underlying proton therapy involves the unique physical properties of protons, particularly their ability to deliver energy to a specific depth within the tissue, known as the Bragg peak. 1 The energy deposition pattern of proton is unique, characterized by a sharp increase in the dose at the Bragg peak, followed by a rapid fall‐off. This sharp dose gradient allows for precise dose distribution, helping eliminate tumors while sparing adjacent healthy tissues. Therefore, proton therapy is particularly suitable for tumors with complex anatomical relationships such as nasopharyngeal carcinoma (NPC). 12 Furthermore, the linear energy transfer (LET) of protons is higher than that of photons, resulting in more complicated DNA double‐strand breaks (DSBs), which are difficult for tumor cells to repair. 13 In addition, the relative biological effectiveness (RBE) of proton therapy is typically high, 14 indicating that proton therapy requires a lower dose than photons to kill cancer cells. Recent studies have found that the relatively low risk of radiation‐induced lymphopenia (RIL) during proton therapy may be attributed to a smaller radiation field size and lower radiation dose. 15

Comparison of proton therapy with conventional radiotherapy

Proton therapy has three major advantages over conventional radiotherapy. (i) Reduced radiation exposure: Proton therapy significantly decreases radiation exposure to healthy tissues, which is especially beneficial to pediatric populations, who are at a higher risk of long‐term side effects from radiation. Patients with medulloblastoma who received proton therapy reportedly exhibit improved neurocognitive outcomes and fewer secondary malignancies than those treated with traditional photon therapy. 16 , 17 (ii) Precise irradiation: Proton therapy delivers higher doses to tumors while minimizing exposure to the surrounding organs at risk, improving local control rates in various malignancies such as HNSCC, central nervous system cancer, and prostate cancer. 2 (iii) Reduced radiation‐induced immunosuppression: Radiation‐induced immunosuppression significantly hinders the effectiveness of anti‐tumor treatments, and proton therapy alleviates this condition in NSCLC and HNSCC. 18 , 19 Notably, the mechanisms by which protons induce tumor cell death differ from those associated with photon therapy, leading to distinct phenotypes. This has been thoroughly reviewed by Nikitaki et al. 13 Despite these advantages, the high cost of proton therapy facilities and limited availability of treatment centers remain the main barriers to its widespread adoption. 20

Applications of proton therapy in different tumor types

The idea of utilizing protons for cancer treatment was first proposed by Robert R. Wilson 21 in 1946, and the first patients received treatment in 1954. 22 Subsequently, proton therapy was used to treat various tumor types because of its versatility and effectiveness. 2 In recent years, proton therapy for HNSCC has shown promising results in reducing irradiation‐induced toxicities, thereby improving patients’ quality of life. 23 In 2025, proton therapy was also used to treat head and neck mucosal melanoma, conjunctival malignant melanoma, and endometrial cancer. 24 , 25 , 26 , 27 Additionally, proton therapy has been investigated for its potential in treating primary hepatic and pancreatic cancers, in which its dosimetric advantages can lead to improved outcomes. 28 Notably, in addition to eliminating the first malignancy, proton therapy also showed potential to prevent a second malignancy, which is one of the most serious late effects of radiation therapy. 29 For example, a retrospective cohort study involving nine pediatric patients with low‐grade brain tumors indicated that proton therapy was associated with lower incidence of second malignancy and mortality, compared with photon therapy at the same dosage. 30 Further research suggests that proton therapy could benefit patients with brain tumors because it can bypass traditional oxygen dependence. 31 Several reviews and clinical studies have identified the role of proton therapy in the treatment of lung cancer, 32 , 33 triple‐negative breast cancer, 34 and esophageal cancer. 35 As clinical evidence continues to accumulate, the role of proton therapy in the treatment of various malignancies is expected to expand, with ongoing research targeting the optimization of treatment protocols and exploring combination therapies to enhance efficacy. 2 Notably, proton irradiation induces distinct transcriptional profiles in various tumors, thereby shedding light on the underlying mechanisms (Table 1).

GEO ID | Tumor Types | Researcher | Publication Year
GSE149023 | Breast Cancer | Cammarata et al.36 | 2020
GSE116325 | Breast Cancer | Bravatà et al.37 | 2019
GSE103472 | Breast Cancer | Bravatà et al.38 | 2018
GSE162986 | Glioblastoma | Bravatà et al.39 | 2021
GSE127989 | Glioblastoma | Cammarata et al.40 | 2019
GSE192817 | Glioblastoma, Head and Neck Cancer, Prostate Cancer | Schniewind et al.41 | 2022
GSE90761 | Head and Neck Cancer | Lupu‐plesu et al.42 | 2017
GSE45609 | Lung Cancer | Beheshti et al.3 | 2014
GSE107444 | Pancreatic Cancer | Fujinaga et al.43 | 2019