Treatment of malignant tumors has always been a worldwide challenge. The complexity, diversity, and heterogeneity of tumors have prompted the treatment strategies to gradually shift from monotherapy to combination therapy that can synergize multiple treatment modalities. With unique physical and chemical properties, nanomaterials have been widely used in different cancer therapies, including chemotherapy, immunotherapy, and phototherapy. Especially, the variability and integrity of nanomaterials make them ideal media for synergistic collaboration strategies. Here, we provide our perspective on the synergistic strategy of nanoplatform-mediated phototherapies and related combination therapies, specifically photochemotherapy, photoradiotherapy, and photoimmunotherapy. Besides, we provide an analysis and outlook on the current challenges faced by synergistic nanophototherapy.
Cancer is one of the major causes of death, with high incidence and mortality in the world, and is expected to continue increasing in the following 20 years. Over the past few decades, tremendous efforts have been made toward exploring rapid, safe, and effective approaches for cancer diagnosis and treatment. Precision surgery, intensity-modulated radiation therapy, and radiofrequency ablation are commonly used in clinical treatments for primary tumors . Chemotherapy and immunotherapy with molecule targeting have made much progress in controlling distant metastases [2, 3]. The survival time of patients with localized tumor is significantly prolonged, while that of patients with distant metastases is still short. For instance, the five-year relative survival for patients with breast or prostate tumors decreased from 99 to 20–30% when the tumors progressed from localized tumors to distant metastases . Monotherapy is difficult to achieve complete cure in malignant tumors, even causing drug resistance and severe side effects. Developing collaborative strategies of different treatments for both primary tumors clearance and distant metastases elimination is urgently required.
The rapid development of nanotechnology marks a big step forward in cancer therapy. Nano-sized materials hold the preference to passively accumulate in solid tumors rather than normal tissues during blood circulation due to the enhanced permeability and retention effect . Additionally, nanomaterials can be functionalized with specific ligands to target tumor cells, which have been employed in chemotherapy and immunotherapy . Moreover, with the outstanding optical and physical properties, nanomaterials have great advantages in photoimaging and phototherapy . The above-mentioned benefits ensure that nanomaterials become ideal media for participating in combination therapy, with not only additive but also synergistic effect, guiding a promising direction in the field of cancer therapy. Notably, researchers have been exploring multifunctional nanomaterials to combat cancer based on their distinct properties, leading to the control of primary and distal tumors (Figure 1).
Nanomaterial-based photodiagnosis and phototherapy have been extensively applied in preclinical and clinical cancer research [8, 9]. Under the light irradiation of appropriate wavelength, nanomaterials can convert light energy into heat for photothermal therapy (PTT) or generate cytotoxic reactive oxygen species (ROS) for photodynamic therapy (PDT). Besides, nanomaterials show the ability to generate acoustic waves for photoacoustic imaging (PAI) and fluorescence emission for fluorescence imaging (FI), which can be utilized in diagnosis and/or imaging-guided therapy (Figure 2). Inorganic nanomaterials are commonly used as photoagents, due to their strong optical absorption, high photothermal conversion efficiencies, and high quantum yields in ROS generation . The absorption caused by surface plasmon resonance of nanogold particles can be adjusted by tuning their shape and size, forming sphere, rod, and shell-shapes, which have been widely explored in the fields of PTT, PAI, and PAI-guided PTT [7, 11]. Especially, AuroShells, the nanogold coated-tiny silica spheres, were used in clinical study for the treatment of prostate cancer. AuroShells-mediated PTT achieved successful responses without relapse within 12 months in 15/16 of patients .
However, the laser intensity significantly attenuates as the penetration depth increases, resulting in unsatisfactory diagnosis and treatment of deep tumors. Consequently, light-responsive nanomaterials in the second near infrared (NIR) bio-window were explored, which is helpful to present a solution for deep-tissue therapy . Besides, in order to improve the control of nanomaterial-based cancer phototherapy, accurate local irradiation under imaging guidance will be considered . On the other hand, with the development of endoscopic optical fiber and interventional technology, minimally invasive treatments in situ for visceral tumors can be developed .
Despite of great therapeutic efficacy on localized tumors, mono-PTT can hardly achieve satisfactory therapeutic response in advanced tumors, because of incomplete clearance of residual tumors, which ultimately leads to tumor recurrence and metastasis. Therefore, it is necessary to make a combination between PTT and other therapies to obtain synergistic and desired results at a lower dosage of each therapy. Depending on the laser dosage, PTT can promote accumulation and penetration of drug carriers in tumor, trigger drug release, and enhance drug sensitivity, so as to reduce the side effects and overcome drug resistance of chemotherapy. Simultaneously, chemotherapy can treat metastases beyond the range of laser irradiation, and enhance primary tumors elimination by PTT. For example, CuS-RNP/DOX@PEI, a twice NIR light-triggered thermo-responsive smart switch, was constructed for a potential photo-chemo synergistic therapy . The first NIR light irradiation could effectively release doxorubicin (DOX) in targeted tumors, which enhanced efficacy of subsequent PTT under the second NIR light irradiation. Moreover, a series of sophisticated and orchestrated nanomaterials have been developed to demonstrate the effects of photochemotherapy in a highly spatial and temporal manner. The efficacy of PDT and radiotherapy (RT) can be optimized by mild PTT through increasing the oxygen perfusion to reverse hypoxia or low oxygen concentration in tumor microenvironment (TME) . Photoagents containing high-Z elements can serve as radiosensitizers, such as Bi nanoparticles, which can be employed to combine PTT/PDT/RT with a single nanomaterial for synergistic phototherapy .
In spite of phototherapy has bright future as a precise cancer treatment modality for localized tumors, it has restrictions in controlling distant metastases and preventing tumor recurrence. Immunotherapy can stimulate host immune system to destroy cancer cells and reverse TME from “cold” to “hot”. In 2011, Ralph Steinman was awarded the Nobel Prize for the discovery of dendritic cells (DCs) and investigation of its function in adaptive immunity, which facilitated the development of DC vaccines . James Allison and Tasuku Honjo were awarded the Nobel Prize in 2018 for the discovery of novel cancer immunotherapies that inhibit negative immune regulation by immune checkpoint inhibitors of cytotoxic T lymphocyte associated antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) [20, 21]. Although many immunotherapies have had encouraging clinical outcomes, satisfactory tumor inhibition has been achieved only in a small number of patients with advanced cancer. To address the intractable nature of cancer, photo-nano-immunotherapy was proposed to induce synergistic effect for both primary tumors killing and distant metastases controlling [22, 23].
Light-responsive nanomaterials can ablate primary tumors to release various immune stimuli, such as tumor-associated antigens, damage-associated molecular patterns and proinflammatory cytokines, which could be recognized by DCs. Such a process known as immunogenic cell death produced an in situ whole tumor cell vaccine. Following phototherapy, nanomaterials have been utilized in the processes of DCs maturation and antigen presentation to amplify the vaccine effect. During the processes, immunoadjuvants were often introduced, such as oligodeoxynucleotides (CpG)-loaded hollow CuS nanoparticles, which were able to promote DCs maturation and amplify systemic antitumor immunity . This endogenous vaccination strategy, based on synergistic phototherapy and immunotherapy, may offer a potentially effective way to treat cancer (Figure 3). Moreover, TME would be remodeled and infiltrated cytotoxic T lymphocytes could be activated for tumor cells killing after additional introduction of immune checkpoint blockades. For instance, glycated chitosan coated single-walled carbon nanotubes and indocyanine green/imiquimod co-loaded nanoparticles have been prepared to combine with CTLA-4 checkpoint inhibitors for the treatment of 4T1 murine breast cancer [25, 26]. In addition, to obtain desirable treatment outcomes of malignant tumors, a combination of phototherapy and multiple therapies has been developed. For example, reduced graphene oxide (rGO) coated methotrexate (MTX, a chemotherapeutic agent) and SB-431542 (SB, a transforming growth factor beta inhibitor) were constructed for photo-chemo-immunotherapy to trigger systemic antitumor immunity and resist rechallenge in the mice model of breast cancer . To be specific, photoreleased MTX synergized with rGO-based PTT for in situ vaccination, which enhanced by remodeled TME with SB, finally eradicating primary tumors as well as metastases.
Summarily, the combination of nanomaterial-based phototherapy with other therapeutic approaches, i.e., photochemotherapy, photoradiotherapy, and photoimmunotherapy, has been proven to have strong prospects in enhancing therapeutic efficacy. It is worth highlighting that photoimmunotherapy, a well-established and prominent combination therapy, has the capability to effectively eliminate targeted tumors, residual tumors and metastases, as well as trigger host immune memory to prevent tumor recurrence. Specially, employing immunoadjuvant after PTT has shown the synergism in clinical treatment of patients with advanced melanoma or breast cancer, resulting in elimination of primary tumors and shrinking of pulmonary metastases, with prolonged survival time and improved quality of life [28, 29]. However, there are still several challenges of nanomaterial-based synergistic phototherapy in translating preclinical success into clinical application. Firstly, the safety, uniformity, degradability, and biocompatibility of nanomaterials should be carefully considered to meet the need of clinical applications. Current nanomaterials used in phototherapy and other related combination modalities are generally integrated and sophisticated. For clinical applications, a large scale of nanomaterials synthesis with highly quality control will be required. In this regard, efforts have been devoted into exploring nanomaterials with simpler synthesis. Besides, research on long-term human toxicology should be strengthened to guarantee the safety of clinical applications. Secondly, regarding intravenous injection, nanomedicines can be captured by the reticuloendothelial system during circulation and then cleared from the host, resulting in only a fraction of drugs reaching tumor lesion. The challenges can be met by employing targeting ligands, coating biomimetic cell membrane or intratumor delivery. In addition, better understanding of the interaction between nanomaterials and tissues, organs and tumors would render better guidance for development of nanomaterial-based therapy. Last but not the least, although tumor-associated antigens produced by phototherapy as in situ autologous tumor vaccine has opened a novel avenue for primary tumors eradication and metastases inhibition, most of the relevant studies have been limited to animal experiments and lack of thorough understanding of potential mechanisms. Additionally, to achieve admirable outcomes with minimal side effects, the administration dose, timing and sequence of combinatorial nanodrugs are imperative to be determined. Thus, great efforts need to be made to clarify the mechanism for both individual phototherapy and related combination therapy, which will benefit for further studies about synergistic therapy and clinical translation.
In conclusion, overcoming the drawbacks and limitations of mono-phototherapy makes combination strategies a promising cancer treatment modality that warrants further attention. Benefiting from the inherent optical, physical, and chemical properties, nanomaterials are capable to be endowed with various functions, which will further improve the relationship between different treatment modalities to achieve synergistic combination therapy. More and more efforts have been put into revealing the potential of nanomaterials in combination therapy, providing a solid foundation for their translation from bench to bedside.
Funding source: National Key Research and Development Program of Chinahttp://dx.doi.org/10.13039/501100012166
Award Identifier / Grant number: 2018YFB0407200
Funding source: Guangdong Province Key Area R&D Program
Award Identifier / Grant number: 2019B110233004
Funding source: Hainan University
Award Identifier / Grant number: KYQD(ZR)20074
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: This study was supported by grants from National Key Research and Development Program of China (No. 2018YFB0407200) (X.L.), Guangdong Province Key Area R&D Program 2019B110233004 (F.Z.), and Hainan University R&D Program (KYQD(ZR)20074) (F.Z.).
Conflict of interest statement: The authors declare no conflicts of interest regarding this article.
 V. T. DeVitaJr., A. M. M. Eggermont, S. Hellman, and D. J. Kerr, “Clinical cancer research: the past, present and the future,” Nat. Rev. Clin. Oncol., vol. 11, pp. 663–669, 2014, https://doi.org/10.1038/nrclinonc.2014.153. Search in Google Scholar
 L. Zhong, Y. Li, L. Xiong, et al.., “Small molecules in targeted cancer therapy: advances, challenges, and future perspectives,” Signal Transduct. Tar., vol. 6, p. 201, 2021, https://doi.org/10.1038/s41392-021-00572-w. Search in Google Scholar
 S. Y. van der Zanden, J. J. Luimstra, J. Neefjes, J. Borst, and H. Ovaa, “Opportunities for small molecules in cancer immunotherapy,” Trends Immunol., vol. 41, pp. 493–511, 2020, https://doi.org/10.1016/j.it.2020.04.004. Search in Google Scholar
 D. Kalyane, N. Raval, R. Maheshwari, V. Tambe, K. Kalia, and R. K. Tekade, “Employment of enhanced permeability and retention effect (EPR): nanoparticle-based precision tools for targeting of therapeutic and diagnostic agent in cancer,” Mater. Sci. Eng. C Mater., vol. 98, pp. 1252–1276, 2019, https://doi.org/10.1016/j.msec.2019.01.066. Search in Google Scholar
 W. Alshaer, H. Hillaireau, and E. Fattal, “Aptamer-guided nanomedicines for anticancer drug delivery,” Adv. Drug Deliv. Rev., vol. 134, pp. 122–137, 2018, https://doi.org/10.1016/j.addr.2018.09.011. Search in Google Scholar
 Y. Liu, P. Bhattarai, Z. Dai, and X. Chen, “Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer,” Chem. Soc. Rev., vol. 48, pp. 2053–2108, 2019, https://doi.org/10.1039/c8cs00618k. Search in Google Scholar
 H. Chen, W. Zhang, G. Zhu, J. Xie, and X. Chen, “Rethinking cancer nanotheranostics,” Nat. Rev. Mater., vol. 2, p. 17024, 2017, https://doi.org/10.1038/natrevmats.2017.24. Search in Google Scholar
 X. Li, J. F. Lovell, J. Yoon, and X. Chen, “Clinical development and potential of photothermal and photodynamic therapies for cancer,” Nat. Rev. Clin. Oncol., vol. 17, pp. 657–674, 2020, https://doi.org/10.1038/s41571-020-0410-2. Search in Google Scholar
 Y. Ju, B. Dong, J. Yu, and Y. Hou, “Inherent multifunctional inorganic nanomaterials for imaging-guided cancer therapy,” Nano Today, vol. 26, pp. 108–122, 2019, https://doi.org/10.1016/j.nantod.2019.03.006. Search in Google Scholar
 H. Tang, X. Xu, Y. Chen, et al.., “Reprogramming the tumor microenvironment through second-near-infrared-window photothermal genome editing of PD-L1 mediated by supramolecular gold nanorods for enhanced cancer immunotherapy,” Adv. Mater., vol. 33, p. e2006003, 2021, https://doi.org/10.1002/adma.202170086. Search in Google Scholar
 A. R. Rastinehad, H. Anastos, E. Wajswol, et al.., “Gold nanoshell-localized photothermal ablation of prostate tumors in a clinical pilot device study,” Proc. Natl. Acad. Sci. USA, vol. 116, pp. 18590–18596, 2019, https://doi.org/10.1073/pnas.1906929116. Search in Google Scholar
 C. Xu and K. Pu, “Second near-infrared photothermal materials for combinational nanotheranostics,” Chem. Soc. Rev., vol. 50, pp. 1111–1137, 2021, https://doi.org/10.1039/d0cs00664e. Search in Google Scholar
 P. Cheng and K. Pu, “Activatable phototheranostic materials for imaging-guided cancer therapy,” ACS Appl. Mater. Interfaces, vol. 12, pp. 5286–5299, 2020, https://doi.org/10.1021/acsami.9b15064. Search in Google Scholar
 F. Zhou, J. Yang, Y. Zhang, et al.., “Local phototherapy synergizes with immunoadjuvant for treatment of pancreatic cancer through induced immunogenic tumor vaccine,” Clin. Cancer Res., vol. 24, pp. 5335–5346, 2018, https://doi.org/10.1158/1078-0432.ccr-18-1126. Search in Google Scholar
 C. Chen, Y. Ma, S. Du, et al.., “Controlled CRISPR-Cas9 ribonucleoprotein delivery for sensitized photothermal therapy,” Small, vol. 17, p. e2101155, 2021, https://doi.org/10.1002/smll.202170169. Search in Google Scholar
 X. Xu, Y. Chong, X. Liu, et al.., “Multifunctional nanotheranostic gold nanocages for photoacoustic imaging guided radio/photodynamic/photothermal synergistic therapy,” Acta Biomater., vol. 84, pp. 328–338, 2019, https://doi.org/10.1016/j.actbio.2018.11.043. Search in Google Scholar
 J. Du, Z. Gu, L. Yan, et al.., “Poly(vinylpyrollidone)-and selenocysteine-modified Bi2Se3 nanoparticles enhance radiotherapy efficacy in tumors and promote radioprotection in normal tissues,” Adv. Mater., vol. 29, p. 1701268, 2017, https://doi.org/10.1002/adma.201701268. Search in Google Scholar
 R. M. Steinman and Z. A. Cohn, “Identification of a novel cell type in peripheral lymphoid organs of mice. I. Morphology, quantitation, tissue distribution,” J. Exp. Med., vol. 137, pp. 1142–1162, 1973. https://doi.org/10.1084/jem.137.5.1142. Search in Google Scholar
 M. F. Krummel and J. P. Allison, “CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation,” J. Exp. Med., vol. 182, pp. 459–465, 1995, https://doi.org/10.1084/jem.182.2.459. Search in Google Scholar
 Y. Ishida, Y. Agata, K. Shibahara, and T. Honjo, “Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death,” EMBO J., vol. 11, pp. 3887–3895, 1992, https://doi.org/10.1002/j.1460-2075.1992.tb05481.x. Search in Google Scholar
 C. W. Ng, J. Li, and K. Pu, “Recent progresses in phototherapy-synergized cancer immunotherapy,” Adv. Funct. Mater., vol. 28, p. 1804688, 2018, https://doi.org/10.1002/adfm.201804688. Search in Google Scholar
 Y. Li, X. Li, F. Zhou, et al.., “Nanotechnology-based photoimmunological therapies for cancer,” Canc. Lett., vol. 442, pp. 429–438, 2019, https://doi.org/10.1016/j.canlet.2018.10.044. Search in Google Scholar
 L. Guo, D. D. Yan, D. Yang, et al.., “Combinatorial photothermal and immuno cancer therapy using chitosan-coated hollow copper sulfide nanoparticles,” ACS Nano, vol. 8, pp. 5670–5681, 2014, https://doi.org/10.1021/nn5002112. Search in Google Scholar
 Y. Li, X. Li, A. Doughty, et al., “Phototherapy using immunologically modified carbon nanotubes to potentiate checkpoint blockade for metastatic breast cancer,” Nanomed. Nanotechnol., vol. 18, pp. 44–53, 2019. https://doi.org/10.1016/j.nano.2019.02.009. Search in Google Scholar
 Q. Chen, L. Xu, C. Liang, C. Wang, R. Peng, and Z. Liu, “Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy,” Nat. Commun., vol. 21, p. 13193, 2016, https://doi.org/10.1038/ncomms13193. Search in Google Scholar
 F. Zhou, M. Wang, T. Luo, J. Qu, and W. R. Chen, “Photo-activated chemo-immunotherapy for metastatic cancer using a synergistic graphene nanosystem,” Biomaterials, vol. 265, p. 120421, 2021, https://doi.org/10.1016/j.biomaterials.2020.120421. Search in Google Scholar
 M. F. Naylor, F. Zhou, B. V. Geister, R. E. Nordquist, X. Li, and W. R. Chen, “Treatment of advanced melanoma with laser immunotherapy and ipilimumab,” J. Biophotonics, vol. 10, pp. 618–622, 2017, https://doi.org/10.1002/jbio.201600271. Search in Google Scholar
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