Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive soft-tissue sarcomas that arise within peripheral nerves. MPNSTs, which affect approximately 10% of patients with neurofibromatosis type 1 (NF1) and cause severe organ damage, are associated with high morbidity (Mowery and Clayburgh, 2019; Widemann, 2009). Chemotherapy and radiotherapy provide only limited benefits to MPNST patients, and there is no targeted therapy approved for clinical use (Vitolo et al., 2019; van Noesel et al., 2019; Kroep et al., 2011). The key to improving the prognosis of MPNST patients is extended resection with negative surgical margins, which still faces problems such as the difficulty of surgery, high risk of local recurrence, and distant metastasis (Widemann and Italiano, 2018). There is thus a very large unmet medical need to develop efficient therapeutic strategies for MPNSTs.

Photothermal therapy (PTT), a minimally invasive, highly specific, and temporally and spatially selective local treatment modality, has gained increasing attention in the field of cancer theranostics, including for the treatment of MPNSTs (Huang and Lovell, 2017). Traditional PTT contains two elements: photothermal agents (PTAs) and lasers. PTAs can be grouped into inorganic and organic materials. Inorganic PTAs include noble metal materials (e.g., Au, Pd, Pt, etc.) (Tang et al., 2014; Shi et al., 2016a), metal chalcogenide materials (e.g., Ag₂S, CuS, Cu_2-xSe, etc.) (Sheng et al., 2018), carbon-based materials (e.g., carbon nanotubes, carbon dots, and graphene) (Xu et al., 2018), and graphene analogs (two-dimensional transition metal carbides/nitrides [MXenes], two-dimensional monoelemental materials [Xenes], hexagonal boron nitride, carbon nitride, and transition metal dichalcogenides) (Luo et al., 2018; Thapa et al., 2016). However, inorganic PTAs have intrinsic issues such as poor biodegradability, disappointing processability, and apparent cytotoxicity. Organic PTAs include mainly small molecules (e.g., cyanine, porphyrin, phthalocyanine, croconaine, boron dipyrromethene, etc.) (Bhattarai and Dai, 2017; Cao et al., 2017; Pan et al., 2019) and semiconducting polymer-based nanoparticles (e.g., polyaniline, polypyrrole, etc.) (Xia et al., 2017; Yang et al., 2018; Ma et al., 2019). Although the advantageous properties of organic agents include distinct biodegradability and biocompatibility, optimization of photothermal conversion efficiency and photothermal stability is highly challenging (Liu et al., 2019). Therefore, both organic and inorganic PTAs significantly hinder the clinical application of PTT (Yuan et al., 2013).

Near-infrared (NIR) lasers, which represent a promising type of PTT-related laser, play significant roles in addressing the demand for superficial tumor therapy due to their biowindow characteristics, which include a lower background signal and higher tissue penetration depth than those of other biowindows (Lin et al., 2017). NIR light can be divided into four distinct regions according to wavelength: NIR-I (700–950 nm), NIR-II (1000–1350 nm), NIR-III (1600–1870 nm), and NIR-IV (2100–2300 nm) (Sordillo et al., 2017). The latest research on light-responsive wavelengths for PTT has focused mainly on NIR-I and NIR-II biowindows in combination with NIR lasers and wavelength-matched PTAs (Guo et al., 2018; Feng et al., 2019). The evidence regarding NIR-III lasers remains comparatively limited in the field of PTT. Compared with NIR-I and NIR-II lasers, NIR-III lasers possess relatively high penetration depths and low optical scattering effects (Horton et al., 2013). The total attenuation lengths of human prostate and breast cancer have been revealed to be higher in the NIR-III optical windows than in the other NIR regions, confirming the potential for application of NIR-III lasers in tumor therapy (Choi et al., 2016).

The majority of MPNSTs are located on the body surface including head, neck, and extremity (Le Guellec et al., 2016). Therefore, it could be boldly speculated that NIR-III laser would effectively induce photothermal ablation of MPNSTs due to their surface layout characteristics. Sordillo et al., 2017 previously demonstrated that NIR-III treatment appears to involve a better wavelength range for tissue containing high collagen than conventional NIR-I treatment. In addition, a previous genetic profiling study has revealed that collagen expression is significantly upregulated in MPNSTs (Karube et al., 2006). Therefore, the photothermal effects of NIR-III could be more concentrated in MPNSTs than in adjacent normal skin and soft tissue. Moreover, the safety of NIR-III has been widely demonstrated in various medical applications, including optical imaging (Shi et al., 2016b), eye disease treatment (Sakimoto et al., 2006), and even cosmetic treatments (Adatto et al., 2017). In summary, the potential therapeutic effectiveness and desirable safety of NIR-III treatment will likely accelerate its clinical application compared with that of traditional photothermal theranostic methods. Although the application of NIR-III for PTT has not yet been demonstrated in MPNSTs, the existing data further strengthen our expectation that NIR-III laser can be used for PTT of tumors without the utilization of PTAs.

In this work, with the aim of reducing the pain of MPNST patients (Figure 1a–b) and avoiding the intrinsic drawbacks of PTAs and the aforementioned critical problems, we performed PTT using a 1650 nm NIR-III laser in a simple manner without the addition of PTAs (Figure 1—figure supplement 1). The relatively high collagen content of MPNSTs ensure the efficiency of photothermal tumor ablation and make the NIR-III laser a suitable and potent therapeutic modality that has potential for use in clinical applications. In principle, the photothermal conversion of the NIR-III laser is attributed to the thermal molecular movement of the irradiated object after laser irradiation. In addition, the power safety limit for the NIR-III laser is higher than that for NIR-I and NIR-II lasers, which in turn leads to efficient and safe tumor ablation (Figure 1c–d). Both in vitro and in vivo results indicate that the photothermal conversion ability of the NIR-III laser is enough to rapidly ablate cancer cells, which affirms the antineoplastic effect of NIR-III PTT. This PTAs-free PTT strategy possesses unique advantages for the development of clinical application and the improvement of patient prognosis due to the excellent biocompatibility and predominant photothermal conversion efficiency of NIR-III laser.

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The 1650 nm NIR-III laser used in this work was composed of laser diodes, a collimator lens, a photodetector, a spectroscope, focusing lenses, and an optical fiber interface (Figure 2a). The relevant laser parameters are listed in Supplementary file 1. The photothermal effectiveness of the NIR-III laser was initially evaluated by measuring the temperature changes of an aqueous solution. A schematic diagram and the equipment are shown in Figure 2b. The temperature of the aqueous solution increased gradually with increasing irradiation time and power density (Figure 2c–d). Notably, the 1.5 W cm^–2 laser caused an ~40°C temperature increase within 10 min.

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To further distinguish the photothermal efficiencies of lasers in different biowindows, the temperature changes of aqueous solutions irradiated by NIR-I (808 nm) and NIR-II (980 and 1064 nm) lasers at different power densities were also recorded. For the NIR-I group, adjustment of the laser power had a negligible effect on the change in aqueous solution temperature (Figure 2—figure supplement 1). In contrast, in the NIR-II group, an increase in power density elevated the aqueous solution temperature to a certain extent. However, the maximum temperature difference was controlled within 15°C regardless of the duration (Figure 2—figure supplements 2 and 3). The results above confirm the excellent photothermal performance of the NIR-III laser in comparison to traditional NIR-I and NIR-II lasers.

The NIR-III laser must penetrate skin and subcutaneous fat before it can produce a tumor ablation effect. Therefore, we further evaluated the tissue penetration capability of the NIR-III laser using different biological tissue models (Figure 3a). First, the dependence of the temperature increment on power density was evaluated in chicken breast models (Figure 3b and c). The temperature of the chicken breast surface rapidly increased from 27.2°C to 76.7°C within 10 min under NIR-III laser irradiation (1.5 W cm^–2). In addition, the results of photothermal penetration experiments further validated the highly efficient photothermal performance of the NIR-III laser, as shown in Figure 3d and e. The difference between the temperature at 0 s and the temperature at 600 s (ΔT) was still over 10°C even when a chicken breast of 10 mm thickness was used to block the radiation. Similar results were obtained in the pig fat penetration experiments, namely, the extent of the temperature change was proportional to the power density and inversely proportional to the fat thickness (Figure 3f–i). Notably, temperature range (36.6–91.1°C) varied with laser power and fat thickness. In addition, the temperature alterations at various tissue depths indicated that similar attenuation of photothermal efficiency could be obtained regardless of whether the biological tissue was chicken breast or pig fat (Figure 3j).

Figure 3

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Two representative MPNST cell lines, STS26T and S462, were utilized for in vitro experiments. First, the influences of power density and irradiation time on the anticancer efficacy of the NIR-III laser were assessed in STS26T cells (Figure 4a). In the 5 min group, the 0.25 W cm^–2 NIR-III laser induced a 25% reduction in cell viability, while lasers with higher power density all exhibited a strong killing effect. In the 10 min group, NIR-III irradiation caused maximum cell death regardless of the power density. In addition, the tumor killing efficiency of the NIR-III laser at different penetration depths was also evaluated. The NIR-III laser (1 W cm^–2) demonstrated almost 100% cell killing efficiency after penetrating chicken skin thickness of 4 mm (Figure 4b). Similar results were obtained in the S462 cell groups (Figure 4c and d). A significant increase in S462 cell viability was observed with a chicken skin thickness of 6 mm. For a more thorough examination, calcein-AM/propidium iodide (PI) assays were implemented to investigate the relationship between power density/irradiation time and cell viability. The results demonstrated that significant cell death occurred in NIR-III (0.5 W cm^–2, 5 min) group, the NIR-III (1 W cm^–2, 2 min) group, and the NIR-III (1 W cm^–2, 5 min) groups in both STS26T and S462 cells (Figure 4e and f, Figure 4—figure supplement 1). In addition, consistent results were obtained through flow cytometric analysis. For the NIR-III (1 W cm^–2, 2 min), NIR-III (1 W cm^–2, 5 min), NIR-III (1 W cm^–2, 10 min), NIR-III (0.5 W cm^–2, 5 min), and NIR-III (0.5 W cm^–2, 10 min) groups, the late apoptotic and dead cell populations reached almost 100%, confirming the outstanding photothermal ablation effect of the NIR-III laser (Figure 4g and h). To support clinical applications, the optimal power density and irradiation time should be investigated to maximize the tumor ablation efficiency of the NIR-III laser.

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STS26T and S462 MPNST xenograft mouse models were constructed to explore the capacity of the NIR-III laser at 0.5 and 1.0 W cm^–2 to alter temperature and achieve photothermal ablation in vivo, as shown in Figure 5a–d. In the STS26T xenograft model (Figure 5a and b), the tumor temperature increased from 32.9°C and 33.9°C to 60.2°C and 75.4°C within 10 min of irradiation at the low (ΔT=27.3°C) and high (ΔT=41.5°C) power densities, respectively. Additionally, after adjustment of the laser power density and irradiation time, similar increasing trends were observed in the S462 xenograft group for the low (ΔT=18.6°C) and high (ΔT=30.7°C) power densities (Figure 5c and d). The excellent photothermal performance in vivo further affirms the potential of the NIR-III laser.

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To further evaluate the in vivo tissue penetration depth of NIR-III photothermal ablation, STS26T xenograft tissues were dissected, and histological changes, apoptosis, and cell proliferation were observed at different depths (Figure 5e). It was revealed that effective photothermal ablation of subcutaneous xenograft tumors could be achieved at a depth of 4.5 mm in the NIR-III (0.5 W cm^–2, 10 min) group. However, in the NIR-III (1 W cm^–2, 10 min) group, the effective photothermal ablation depth was over 7.5 mm, as revealed by hematoxylin and eosin (H&E) staining, Ki-67 immunohistochemical staining, and Cleaved-Caspase 3 immunohistochemical staining (Figure 5f–h) and the corresponding statistic analysis (Figure 5—figure supplement 1). Therefore, it could be concluded that a higher power density is correlated with better therapeutic efficiency and outcomes.

To simultaneously evaluate the efficacy and safety of NIR-III PTT, further in vivo PTT experiments were conducted when the tumor volume reached approximately 100 mm³. The STS26T tumor-bearing mice were divided into three groups: the control group, the NIR-III (0.5 W cm^–2, 5 min), group and the NIR-III (1 W cm^–2, 5 min) group. The tumor volume of each mouse was recorded every other day (Figure 6a). Two days after photothermal ablation treatment, the tumors in the two treated groups could no longer be observed with the naked eye and had been replaced by black scars. However, four out of seven mice in the NIR-III (0.5 W cm^–2, 5 min) group had tumor recurrence after 15 days. In comparison, the tumors in the NIR-III (1 W cm^–2, 5 min) group were completely eradicated (Figure 6b and c). In conclusion, the long-term effectiveness evaluation confirmed that the NIR-III (1 W cm^–2, 5 min) treatment group had the best outcome in terms of survival rate in STS26T tumor-bearing mice (Figure 6d and e). Pathological changes revealed by H&E staining and TdT-mediated dUTP-biotin nick and labeling (TUNEL) staining in tumor slices are shown in Figure 6g. More necrotic regions were observed in the NIR-III (1 W cm^–2, 5 min) group than in the NIR-III (0.5 W cm^–2, 5 min) group. In addition, apoptosis occurred in the NIR-III (0.5 W cm^–2, 5 min) group according to TUNEL assays, but the apoptosis in the NIR-III (1 W cm^–2, 5 min) group was more obvious (Figure 6—figure supplement 1).

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Furthermore, to test the biosafety of NIR-III treatment, major organs, including the heart, liver, spleen, lungs, and kidneys were collected, and sliced for H&E staining (Figure 6—figure supplement 2). No significant pathological toxicity was observed in the two groups treated with PTT, and all of the mice demonstrated negligible weight fluctuations (Figure 6f), confirming that NIR-III-induced photothermal ablation had negligible adverse effects.

To explore the underlying mechanisms of the effects of NIR-III treatment, whole-transcriptome sequencing was performed on S462 and STS26T xenograft tumors from the control, NIR-III (0.5 W cm^–2, 5 min), and NIR-III (1 W cm^–2, 5 min) groups. In STS26T tumors, significant transcriptional alterations were observed and were further analyzed (Figure 7a). Both upregulated and downregulated overlapping mRNAs were found in the NIR-III (0.5 W cm^–2, 5 min) group and the NIR-III (1 W cm^–2, 5 min) group compared with control group (Figure 7b). According to Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, the protein processing in endoplasmic reticulum (ER) pathway (hsa04141) were among the most enriched pathways (Figure 7c). Gene Ontology (GO) enrichment analysis of the genes related to the protein processing in ER pathway (hsa04141) was further performed, which revealed that the key biological processes including the ubiquitin-dependent protein catabolic process, the response to unfold protein were enriched, indicating that NIR-III treatment could lead to ER stress in STS26T xenograft tumors (Figure 7d).

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ER stress is a condition during which a variety of pathological conditions including high temperature may impede the capacity of cells to properly fold secretory and transmembrane proteins in the ER and lead to the accumulation of misfolded proteins. Cells with ER stress can initiate a self-protection mechanism termed the unfolded protein response (UPR) that induces a set of transcriptional and translational events to restore ER homeostasis (Qi and Chen, 2019). To explore the specific mechanism, we investigated the interactions between ER pathway-related genes (Figure 7e). It could be found that the key transcription factors regulating the UPR (ATF4 and ATF6B) were among the top upregulated mRNAs related to protein processing in ER pathway (Supplementary file 2). RT-qPCR analysis also confirmed the significant upregulation of ATF4 and ATF6B in the NIR-III (0.5 W cm^–2, 5 min) group and the NIR-III (1 W cm^–2, 5 min) group (Figure 7f). It was demonstrated in previous studies that ATF4 and ATF6B contributed to stress relief and survival by inducing the expression of ER chaperones, which have critical functions in facilitating protein folding and assembly. We identified the most significantly upregulated ER chaperones genes P4HB and HSP1A1 and further confirmed the upregulation of these two genes using RT-qPCR (Figure 7f).

In addition to ER chaperones, the UPR regulated by ATF4 and ATF6 also upregulates the components of ER-associated degradation (ERAD). Proteins that do not properly fold within a certain time are targeted for ERAD, which efficiently retro-translocates them from the ER into the cytosol for degradation via the ubiquitin-proteasome system. According to KEGG enrichment analyses, the ubiquitin-mediated proteolysis pathway (hsa04120) was also enriched (Figure 7c). GO enrichment analyses revealed the related key biological processes including protein polyubiquitination (Figure 7—figure supplement 1a). The interactions between ubiquitin-mediated proteolysis pathway-related genes are shown in Figure 7—figure supplement 1b. The most significantly upregulated mRNAs including UBA3, UBE2E1, and HERC3 were listed in Supplementary file 3.

Therefore, it can be speculated that the ER stress response (ERSR) enabled a proportion of STS26T cells to survive the NIR-III laser treatment through improving protein-folding capacity and ubiquitylating unfolded proteins.

Whole-transcriptome sequencing and corresponding bioinformatics analyses were also performed on S462 cells (Figure 7—figure supplement 2). However, the ER pathway was not enriched in the analyses, indicating that heterogeneity exists in response to NIR-III laser treatment among different MPNST cell types. Notably, STS26T cells exhibited stronger resistance to NIR-III laser treatment than S462 cells, as demonstrated by flow cytometric analysis (Figure 7—figure supplement 3).

In clinic, the main management for MPNSTs is still surgical resection with sufficient margins, which is often highly risky due to expected damage to adjacent nerves and neurovascular bundles. Therefore, it is applicable to combine preoperative NIR-III photothermal laser treatment and surgery to reduce the scope and the risk of surgery. In addition, postoperative local recurrence and distant metastasis are unfavorable factors affecting the outcomes of MPNST patients. The postoperative application of NIR-III laser treatment at the resection margin could be a potent modality to reduce the risk of local recurrence. However, further experiments and clinical studies are necessary for verification of the safety and effectiveness of these clinical applications.

Mechanically, it is possible that STS26T MPNST cells strongly enhanced the protein processing capacity of the ER to survive the ER stress induced by NIR-III laser treatment. The specific mechanism and regulatory networks need to be explored in the future. In addition, it is speculated that the combination of NIR-III laser treatment with an ER stress inhibitor (such as icariin or ghrelin) could potentially increase therapeutic effectiveness (Wang et al., 2019; Li et al., 2019), which should be further verified in future studies. Although the tumor ablation effect is influenced by individual differences in molecular response and treatment efficiency, an optimal effect can still be achieved by optimizing the power density and irradiation time of the NIR-III laser.

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Author details

1. Yihui Gu

   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Data curation, Investigation, Methodology, Writing – original draft

   Contributed equally with

   Zhichao Wang and Chengjiang Wei

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9321-1768

2. Zhichao Wang

   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Data curation, Funding acquisition, Investigation, Methodology, Writing – original draft

   Contributed equally with

   Yihui Gu and Chengjiang Wei

   Competing interests

   No competing interests declared

3. Chengjiang Wei

   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Data curation, Investigation, Methodology, Writing – original draft

   Contributed equally with

   Yihui Gu and Zhichao Wang

   Competing interests

   No competing interests declared

4. Yuehua Li

   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Investigation, Writing - review and editing, Experiments in the revision

   Competing interests

   No competing interests declared

5. Wei Feng

   School of Life Sciences, Shanghai University, Shanghai, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

6. Wei Wang

   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Data curation, Investigation

   Competing interests

   No competing interests declared

7. Meiqi Chang

   State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, China

   Contribution

   Data curation, Investigation, Methodology, Writing – original draft

   For correspondence

   changmeiqi@vip.sina.com

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-2211-4044

8. Yu Chen

   School of Life Sciences, Shanghai University, Shanghai, China

   Contribution

   Conceptualization, Data curation, Supervision, Project administration

   For correspondence

   chenyuedu@shu.edu.cn

   Competing interests

   No competing interests declared

9. Qingfeng Li

   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

   Contribution

   Conceptualization, Supervision, Funding acquisition, Investigation

   For correspondence

   dr.liqingfeng@shsmu.edu.cn

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7822-618X

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