4.1 General information
To some extent, the number of publications is an important indicator for assessing academic research activities and trends. This study reveals the research dynamics and long-term trends in the field of NIR-PIT research by analyzing the annual and cumulative number of publications in the field. In 2011, the first article in the field of NIR-PIT research was published, Mitsunaga et al. (2011) and Kobayashi and Choyke (2019) first reported that NIR-PIT is a newly developed cancer therapy that uses an APC activated by irradiation with NIR light. Target-selective PIT is able to treat cancer based on mAb binding to the cell membrane. The annual and cumulative number of publications related to the field of NIR-PIT show a steady growth in the trend of change over the analyzed timeframe. The sustained growth in the number of publications indicates that the field has gradually matured, with more and more researchers investing in the field, which may lead to more interdisciplinary collaborations and research opportunities as the academic influence continues to expand.
In the country/region network analysis, United States, Japan and China occupy a central position in the collaborative network, suggesting that these countries/regions have significant academic influence in the field. United States has the highest centrality and is involved in the greatest number of international collaborations, and with closer cooperation between countries/regions may lead to more resource sharing and knowledge transfer, thus contributing to the overall advancement of the field. The institutions with the largest number of publications are also from the National Institutes of Health (NIH) in the United States, suggesting that they have significant academic influence in the field and may dominate key research themes and findings. In addition, enhanced support for collaboration between core institutions, particularly in the priority research fields, is recommended to foster deeper collaboration and innovation.
The collaborative network between authors and the close cooperation between core authors may have promoted key research advances in the field. Kobayashi H, as the researcher with the highest number of publications involved, has reported several findings in the field of NIR-PIT therapy for cancer (Kobayashi and Choyke, 2019; Sato et al., 2015), demonstrating positive therapy perspectives in a wide range of cancer types. In addition, the immune mechanism of NIR-PIT for cancer treatment is introduced in detail, photochemical reactions are proposed as a major mechanism of cell death induced by NIR-PIT, it can dramatically alter the physical properties of the reactive molecules (Sato et al., 2018). During treatment, antigens and cellular debris released by cancer cell destruction are recognized by the host immune system, which activates immune cells. This immune activation not only helps to destroy residual cancer cells, but may also generate long-term immune memory, thereby reducing the risk of tumor recurrence (Nagaya et al., 2019). These findings provide the theoretical basis and methodological support for subsequent studies, and make remarkable academic contributions to the development of the field of NIR-PIT. Mitsunaga M, as the researcher with the highest co-citation frequency, demonstrates that his findings have been widely recognized and cited in the field, contributing greatly to the use of NIR-PIT in the treatment of cancer progression, confirmed that PIT induces massive cell death in targeted tumour cells immediately after exposure of NIR light (Mitsunaga et al., 2012).
Journal analysis provides insights into academic fields, journal quality and research dynamics. CANCERS as the journal with the highest number of publications and THERANOSTICS as the journal with the highest impact factor among the journals with the highest number of publications in 10 indicates that these journals have influence and scholarly contributions in the field of NIR-PIT research. NAT MED as the journal with the highest citation frequency among the co-cited journals and the highest impact factor indicates a high academic reputation and influence in the field of NIR-PIT research, and the articles published in this journal are widely cited and recognized in the academic community. The dual map overlay of the journals provides a clear view of the development and evolution of the field of NIR-PIT research, helping researchers and journal editors to understand the dynamics of the field and the direction of development.
The co-cited reference analysis identifies references that have significant impact in a particular field or subject, and the most frequently cited publication in this study was a review article on newly developed photochemistry-based cancer therapy NIR-PIT published in 2019 (Mitsunaga et al., 2011), it provides direction for further research and suggests theoretical frameworks with far-reaching implications. Citation burst analysis assists in identifying documents that have attracted widespread attention over a given period of time, revealing emerging research themes or hotspots. Of the five publications bursting from 2021 to the present, two reported on clinical trials of RM-1929 PIT in rHNSCC (Tahara et al., 2021; Cognetti et al., 2021). Provides support for clinical trial data for NIR-PIT in the treatment of solid tumours with strategic importance for the direction of the research field. These data not only help the medical community and researchers to assess the actual effectiveness of the technology, also provide a scientific basis for further optimizing treatment protocols and guiding clinical practice.
4.2 Research hotspots and trends
In academic documents, keywords not only help in the retrieval of papers, also help to convey the core themes and content of the research. The keyword co-occurrence analysis can be used to identify the research hotspots, main research themes and the interrelation between the application of NIR-PIT in cancer therapy. To understand the correlation between different research themes and the focus of researchers by analyzing the frequently occurring keywords. In this study, we analyzed the keywords in the literature related to the field of NIR-PIT, in which the top 10 keywords in terms of frequency of occurrence, including near-infrared photoimmunotherapy (166), photodynamic therapy (61), monoclonal antibody (58), in vivo (50), cancer (46), expression (31), breast cancer (27), enhanced permeability (24), antibody (23), growth factor receptor (16). On the basis of keyword co-occurrence analysis, keyword clustering analysis and burst analysis were performed to further deeply excavate the research hotspots and research trends of the application of NIR-PIT in cancer treatment.
4.2.1 NIR-PIT vs. PDT
NIR-PIT, as a derivation and optimization of PDT, has obvious advantages, including higher targeting and selectivity, enhanced immune response, reduced systemic side effects and broad applicability (Wakiyama et al., 2021). “Near-infrared photoimmunotherapy” (166), as the most frequently occurring keyword, is clearly a core research area within the research field theme. “Photodynamic therapy” (61) followed closely behind, indicating that PDT still has an important role in the application of NIR-PIT for the treatment of cancer.
NIR-PIT and PDT are both photoexcitation-based cancer treatments that rely on the excitation of photosensitizers to induce cell death, but there are significant differences in the way both work and the treatment efficacy. PDT is based on a photochemical reaction between light-activated molecules or photosensitizers, light and oxygen molecules. PDT involves two individually non-toxic components that combine to induce both cellular and tissue effects in an oxygen-dependent manner (Dolmans et al., 2003). The first component of PDT is the photosensitizer, a light-sensitive molecule localized to the target cells and/or tissues. The second component involves the application of specific wavelengths of light to activate the sensitizer. The photosensitizer transfers energy from light to molecular oxygen to produce reactive oxygen species (ROS) substances. The generated ROS cause oxidative damage to important biomolecules such as cell membranes, proteins and DNA, thus leading to the death of tumour cells (Bacellar et al., 2015). The photosensitizers used in PDT are a class of substances capable of generating ROS under light irradiation, and commonly used photosensitizers include porphyrin compounds, such as photosensitive violet, porphyrin derivatives, and nonporphyrin compounds (Diamond et al., 1972; Forbes et al., 1980). Indocyanine green (ICG) as one of the nonporphyrin photosensitizers used commonly in PDT. ICG relies primarily on the photothermal effect produced by excitation of NIR light, which leads to an increase in local tissue temperature, thereby triggering cell necrosis (Mahmut et al., 2023). In addition, ICG is also commonly used for in vivo imaging and diagnostics, with low photoexcitation efficiency and relatively insufficient targeting. PDT is irradiated with light of a specific wavelength, usually in the range of 600–800 nm (Kwiatkowski et al., 2018; Xiang et al., 2021). PDT causes oxidative damage and death of tumor cells by generating ROS and is usually applied to superficial tumors or tumor surfaces (Cramer et al., 2022). PDT is used as an effective cancer treatment, but there are some side effects and challenges. The most common complications include photosensitivity reactions, skin reactions, risk of infection, and allergic reactions (Aebisher et al., 2024). In the future, there is a need to improve the therapeutic efficacy of PDT and reduce side effects by improving photosensitizers, optimizing light sources, developing individualized treatment plans, and combining other therapeutic approaches.
NIR-PIT is based on three elements, mAb, photosensitizer, and NIR light to achieve accurate targeting of tumor cells, which produces physical effects and immune activation, leading to cell necrosis or immunogenic cell death (ICD) (Maruoka et al., 2020). The frequent occurrence of the keywords “monoclonal antibody” (58) and “antibody” (23) emphasizes the centrality of monoclonal antibody in NIR-PIT. mAb is a type of antibody that can specifically recognize and bind to a particular antigen (Zhou and Mascelli, 2011). In NIR-PIT, mAb is usually designed to target specific antigens on the surface of tumor cells to achieve highly specific recognition of tumors (Mahmut et al., 2023). Currently, research is focused on the development of APC that bind to different tumor markers, and mAb serves as an important carrier for targeted therapy in NIR-PIT. Therefore, antibody engineering and drug design technologies are the future direction of development, and the application of mAb will further promote the precision and efficacy of NIR-PIT, as well as expand the range of application.
Photosensitizers are usually a molecule that can be activated by irradiation with light of a specific wavelength, usually NIR light, and after coupling with a mAb, form a photosensitizer-antibody conjugates. When NIR light irradiates the photosensitizer-antibody conjugates on the surface of a cancer cell, the photosensitizer molecule absorbs light energy, triggering a series of physical effects that immediately induce massive cell death in the targeted tumor cell. IR700 dyes are commonly used as photosensitizers for NIR-PIT, causes direct cell membrane disruption under NIR light irradiation by conjugating tumor cell surface antigens through specific antibodies, inducing ICD, independent of ROS generation (Kobayashi and Choyke, 2019). This makes IR700 more suitable for use in hypoxic tumor microenvironments and enables the activation of anti-tumor immune responses with greater targeting and therapy specificity. The NIR light used in PIT, usually in the 700–900 nm wavelength range, has a good tissue penetration ability and can penetrate deeper into the tumor tissue (Xu et al., 2020). In NIR-PIT, these three elements cooperate with each other to form an effective therapy system. mAb ensures targeted delivery and accumulation of the photosensitizer, enhancing therapy specificity and selectivity. The photosensitizer is excited by NIR light which produces a physical effect that acts directly on the tumor cell membrane, ultimately leading to the destruction of the tumor cells. NIR light is the necessary light source to provide excitation of the photosensitizer and, due to its excellent tissue penetration, allows for the treatment of deep-seated tumors.
In general, PIT and PDT, as two different phototherapy, each has its own specific advantages and areas of application. NIR-PIT generates a synergistic effect of physical effect and immune activation, killing tumor cells by directly damaging the cell membrane through physical effect, while releasing antigens to further activate the systemic immune system. PIT combines the dual effects of local physical damage and systemic immune activation, and may have a more significant lasting killing effect on tumors. Therefore, NIR-PIT is suitable for a variety of solid tumors (Aung et al., 2018; Fukushima et al., 2022a; Matsuoka et al., 2022; Paraboschi et al., 2021), including tumors that are deeply located or difficult to be treated by traditional methods. In contrast, PDT is more suitable for the treatment of superficial tumors with relatively weak targeting and immune activation effects. PIT, despite the promising therapy it has demonstrated, still faces a number of side effects and challenges. Side effects focus on local and systemic reactions, including skin reactions, allergic reactions and immune system side effects. Current challenges include limitations in the depth of penetration of the light source, limitations in the targeting and selectivity of photosensitizers, and differences in individual therapy efficacy and therapy response. Further research and technological advances are needed to improve the treatment efficacy and safety of PIT. Therefore, future research will focus on optimizing photosensitizers, improving light source technology, optimizing the combined application of PIT with other therapeutic methods, forming comprehensive treatment protocols to achieve synergistic effects, and expanding the field of clinical applications of PIT in different diseases.
4.2.2 NIR-PIT in cancer therapy
NIR-PIT, as an emerging approach to therapy, has shown potential application in the therapy of cancer. The frequency of the keyword “in vivo” (50) indicates the importance of the experimental model in the current NIR-PIT research, and in vivo experiments provide the basis for verifying the efficacy and safety of the new technology. The frequency of 24 occurrences of “enhanced permeability” indicates that enhanced drug delivery and tissue penetration are also the focus of current in vivo experiments. In addition, in vivo models serve an indispensable role in promoting the translation of NIR-PIT to the clinic, and researchers should pay attention to the design of rational animal experiments to verify the safety and efficacy of NIR-PIT, and more model-based studies in the future are expected to accelerate the clinical application of this technology.
The high frequency of the keywords “cancer” (46), “breast cancer” (27), “expression” (31), and “growth factor receptor” (16) reflect that NIR-PIT shows promising results in a wide range of cancer types, especially in breast cancer shows good promise. Different types of tumors express specific growth factor receptors, and by targeting these receptors, NIR-PIT can effectively kill tumor cells. With in-depth research on different cancer biomarkers and receptor expression, NIR-PIT is expected to play a role in more cancer types and achieve personalized treatment. The first human Phase 1/2 clinical trial of NIR-PIT using cetuximab-IR700 targeting EGFR in patients with inoperable recurrent head and neck tumours was successfully completed in 2017 (Mitsunaga et al., 2011). In 2020, the first antibody-photosensitizer conjugate, cetuximab saratolacan (previously known as RM-1929, commercial name: Akalux) has now been approved by the Japanese government for the treatment of unresectable locally advanced or recurrent head and neck cancer (Gomes-da-Silva et al., 2020). The use of NIR-PIT in head and neck tumors has become one of the most exemplary and intensively studied fields of this treatment technique. NIR-PIT is in testing as an international phase III clinical trial for locoregional rHNSCC patients (LUZERA-301, NCT03769506), with a fast track designation by the United States Food and Drug Administration (US-FDA) (Yamada et al., 2023), and expected to be approved in a few years. Nishikawa et al. (2022) reported the treatment of two patients with oropharyngeal lesions. Treatment responses were good in both cases with no severe adverse events and no functional disorders observed after HN-PIT. Makino et al. (2024) reported for the first time a case of, NIR-PIT for recurrent salivary duct carcinoma of the parotid gland, non-squamous cell carcinoma (non-SCC) of the head and neck region, and the results suggest that NIR-PIT may be effective in EGFR-positive non-SCC. EGFR expression was present in 71%–79% of salivary gland carcinomas (Locati et al., 2009) and 33.1% of salivary duct carcinomas (Takase et al. 2017), making NIR-PIT a viable strategy for the treatment of local recurrence in this population. The application of NIR-PIT in the treatment of head and neck tumors shows significant promise and distinct advantages, but the current study has a small sample size and limited long-term follow-up data, and larger studies are needed in the future to validate the long-term efficacy and safety of NIR-PIT.
Potential applications of NIR-PIT in other different cancer types. Since NIR light can activate photosensitizers that specifically aggregate in tumor cells without significantly damaging healthy brain tissues, thus realizing precise tumor ablation, this technology is particularly suitable for the treatment of refractory brain tumors such as malignant gliomas. Li et al. (2022a) proposed a novel nanotheranostic for a second near infrared (NIR-II) fluorescence imaging-guided combination PIT of GBM, which provides a new pathway for precision PIT of GBM. Nakamura et al. (2017) evaluated the therapeutic efficacy of NIR-PIT in a transgenic model of human EGFR-expressing spontaneous lung cancer (hEGFR-TL), and showed that the tumour volume ratio was significantly inhibited in the NIR-PIT group compared with control group (p < 0.01), and that NIR-PIT effectively treated a case of a spontaneous lung cancer in a hEGFR-TL transgenic mouse model. Yasui et al. (2021) developed a NIR-PIT technique targeting GPR87, showed that 54% of lung cancers and 100% of MPMs in surgical specimens exhibited high expression of GPR87. It showed therapeutic effects on lung cancer and MPM cell lines in vitro and in multiple models in vivo. NIR-PIT targeting GPR87 is a promising therapeutic approach for the treatment of thoracic cancer. Li et al. (2022b) constructed a hybrid cell model containing MRP1-positive H69AR cells and NIH/3T3 stromal cells, which showed that NIR-PIT successfully targeted and killed tumor cells. More importantly, NIR-PIT also led to a significant increase in tumor permeability, resulting in a 9-fold increase in the accumulation of liposomal doxorubicin (Doxil). Nakamura et al. (2017) developed a new phototherapy targeting Podoplanin (PDPN) for malignant pleural mesothelioma (MPM) using both NIR-PIT and anti-PDPN antibody, NZ-1. An APC consisting of NZ-1 and phthalocyanine dye was synthesized. The results showed that PDPN-targeted NIR-PIT produced significant anti-tumour effects in mouse model of MPM. Several animal model studies have demonstrated the significant inhibitory effect of NIR-PIT on thoracic tumors. Due to the deep location of the tumor and the many surrounding vital organs in thoracic tumors, the penetration depth of NIR light is limited and may be difficult to effectively reach the tumor site. Therefore, continuous development of photosensitizers with better tumor targeting and tissue penetration capabilities, as well as development of more advanced drug delivery systems, such as nanoparticles or targeted delivery systems, are needed in the future to improve the accumulation efficiency of photosensitizers in thoracic tumors. In addition, more large-scale clinical trials and long follow-up studies are needed to evaluate the long-term efficacy and safety of NIR-PIT in thoracic tumors.
The application of NIR-PIT in breast cancer has focused on the subtypes of breast cancer that express specific markers, such as HER2 positivity. Preliminary studies have shown that NIR-PIT is not only effective in reducing tumour volume, it also prevents recurrence and metastasis by inducing activation of the immune system. Yamaguchi et al. (2021) evaluated the efficacy of using the HER2 Affibody-IR700Dye conjugate on HER2 overexpressing breast cancer cells, including cells from brain metastases. Affibody is a small molecule protein with rapid clearance, high imaging contrast and good tumour penetration, as well as the ability to cross the blood-brain barrier, NIR-PIT using Affibodies has the potential to extend NIR-PIT to target cancers, including brain metastases. Further, investigated a combination of NIR-PIT for HER2-positive breast cancer cells (SK-BR3, MDA-MB361, and JIMT1) with HER2 Affibody-IR700Dye conjugate and trastuzumab-IR700Dye conjugate, result show that the combination of NIR-PIT with both HER2 Affibody and trastuzumab extends the targeting of NIR-PIT in HER2-positive breast cancer (Yamaguchi et al., 2021). Yamashita et al. (2023) explored the efficacy potential of NIR-PIT targeting HER2 using trastuzumab-IRDye700DX conjugate (Tra-IR700) in HER2-positive breast cancer. The results showed that NIR-PIT with Tra-IR700 induced highly selective therapy effect in a HER2-positive breast cancer model. NIR-PIT with Tra-IR700 holds promise as a novel treatment for HER2-positive cancers, including breast cancer and other HER2-positive cancers. (Fukushima et al., 2022b) investigated the efficacy of intercellular adhesion molecule-1 (ICAM-1) targeting NIR-PIT in the treatment of triple-negative breast cancer (TNBC). The study found that ICAM-1-targeted NIR-PIT significantly inhibited tumour growth and prolonged survival using a human TNBC xenograft mouse model. Therefore, ICAM-1-targeted NIR-PIT is a promising targeted therapy against TNBC and may be a good candidate for human trials. Although the outcome of NIR-PIT is optimistic in early animal trials, future large-scale and multi-centre clinical trials are needed to verify the efficacy and safety of NIR-PIT in breast cancer, and to provide a foundation for its wide application in the clinic. In addition, with the development of precision medicine, the application of NIR-PIT should be developed in the direction of individualized treatment, requiring tailor-made NIR-PIT treatment protocols based on patient-specific tumour types, molecular characteristics and treatment response, as well as combination therapy strategies, in order to improve the efficacy of the treatment and reduce the side effects.