Nanomaterials-Based Photodynamic Therapy with Combined Treatment Improves Antitumor Efficacy Through Boosting Immunogenic Cell Death

Figures & data

Figure 1 Molecular mechanism of PDT. With the light irradiation, PS is activated from the ground singlet state S₀ to the exited singlet state S₁. By intersystem crossing, they are converted to the excited triplet state T₁. Afterwards, electron transfer from T₁ to biological substrates (type I reaction), or energy transfer to molecular oxygen (type ІІ reaction) that leads to a burst of ROS production.

Figure 2 The process of PDT-triggered antitumor T cell responses via immunogenic cell death and the rational strategies to improve antitumor immune responses. PDT killed cells can release cytokines, which stimulate DCs’ maturation. Mature DCs spontaneously migrate to lymph nodes and present antigens to T cells. After antigen-presenting, effector T cells efficiently migrate to tumor sites and kill cells. The rational strategies of promoting PDT-triggered antitumor immunity include combined PDT with ICD-boosted therapies, decrease immunoregulatory suppression with ITM relief, and increase tumor immunogenicity.

Figure 3 An overview of cancer treatment using the combination of phototherapy and Schematic depiction of the combined therapy of immunotherapy and phototherapy.

Note: Reproduced from Wang M, Rao J, Wang M, et al. Cancer photo-immunotherapy: from bench to bedside. Theranostics. 2021;11(5):2218–2231. doi:10.7150/thno.53056.⁵¹

Table 1 Preclinical Studies of Nanomaterials-Based PDT Combined with ICB

PS	Mediated Nanomaterials	ICB Receptor	Combined ICB Drug	Light Source	Cancer Model	Effectiveness	Ref.
H4TBC	MOF	IDO	INCB24360	650 nm	CT26 and MC38 tumor models	This treatment promoted an efficient inhibition in local and abscopal tumors in a bilateral tumor murine model.	[^Citation84]
Porphyrin	Redox-activatable liposome	IDO	NLG-8189	660 nm	4T1 tumor murine model	The percentage of CD8^+ T cells in the treated tumors significantly enhanced to approximately 10.51%, compared to that in PBS group was about 5.11%.	[^Citation85]
Ce6	iPSs (self-assembly of Ce6 and NLG919)	IDO	NLG919	660 nm	CT26 tumor murine model	The percentages of CD4^+ and CD8^+ T cells in PDT combined immunotherapy achieved 2.3, 5.1-fold higher than that in ICB treatment, which was 1.4, 1.8-fold higher than the PDT treatment.	[^Citation86]
Ce6	UCNPs	CTLA-4	Anti-CTLA4 antibody	980 nm	CT26 tumor murine model	PDT applied with αCTLA-4 provided an outstanding effect in eradicating residual tumors with enduring immune responses, especially curing distant tumors without direct light irradiation.	[^Citation88]
ZnPc	UCNP@SiO2@AuNPs	CTLA-4	Anti-CTLA4 antibody	980 nm	4T1 tumor murine model	The treatment was effective in inhibiting the subcutaneous xenograft tumors with minor side effects.	[^Citation89]
Ce6	M-MONs	CTLA-4	Anti-CTLA4 antibody	660 nm	MCF-7 and 4T1 tumor murine model	The treatment system-induced ICD including DAMPs release, TNF-α, IL-6, and IFN-γ secretion, which promoted DCs maturation, CTLs infiltration, and reduced Tregs activation.	[^Citation90]
Pyrolipid	Zn-pyrophosphate	PD-L1	Anti-PD-L1 antibody	670 nm	4T1 tumor murine model	The combined application of PDT and αPD-L1 resulted in a 92% reduction in tumor volumes compared to the PBS group, indicating a satisfactory efficacy for metastatic tumors.	[^Citation93]
Ce6	Ce6/BMS-202 nanoparticles	PD‐1/PD‐L1	BMS-202	660 nm	4T1 tumor murine model	This therapy offered a long-term immune memory response, which efficiently protected mice from tumor recurrence and metastasis.	[^Citation94]
Pyropheoph-orbide	Cyclodextrin‐grafted hyaluronic acid (HA-CD)	PD-L1	JQ1	671 nm	Panc02-pancreatic tumor model	This study consistently verified that it could elicit a potent antitumor immune response in pancreatic cancer while relieving immunosuppression.	[^Citation96]
IR775	Liposome	PD-L1	Metformin	785 nm	MB49 and CT26 tumor murine models	The weights of collected tumors in the PBS group were 8-fold heavier than that in the NPs + Laser group, indicating this therapy possessed excellent antitumor efficacy for various types of cancers.	[^Citation97]

Figure 4 The anti-metastatic efficacy of porphyrin-phospholipid combined with the IDO inhibitor. (A) Schematic illustration of the preparation of functional liposomes and the mechanism of ICD pathway. (B) Antitumor mechanism of combining PDT with the IDO inhibitor in vivo. (C) Tumor growth was detected by the IVIS imaging system. (D and E) The progress of lung metastasis was observed by the IVIS imaging system. (F) The analysis of lung metastatic nodules’ numbers. **P < 0.01, compared with PBS and IND@RAL without irradiation groups; ***P < 0.001, compared with PBS and IND@RAL without irradiation groups. (G) H&E stained images of lungs. Scale bar = 100 μm.

Note: Reprinted with permission from Liu D, Chen B, Mo Y, et al. Redox-Activated Porphyrin-Based Liposome Remote-Loaded with Indoleamine 2,3-Dioxygenase (IDO) Inhibitor for Synergistic Photoimmunotherapy through Induction of Immunogenic Cell Death and Blockage of IDO Pathway. Nano Lett. 2019;19(10):6964–6976. doi:10.1021/acs.nanolett.9b02306. Copyright 2019 American Chemical Society.⁸⁵

Figure 5 Different PD-L1/PD-1 blockade strategy combined with PDT to better cure cancer. (A) Schematic description of NPs fabricated by the electronic interaction of AD-SS-JQ1, HA-CD, and AD-SS-PPa. (B) The expected mechanism of NPs triggered a combination of PDT with immunotherapy for pancreatic cancers. Reproduced from Sun F, Zhu Q, Li T, et al. Regulating Glucose Metabolism with Prodrug Nanoparticles for Promoting Photoimmunotherapy of Pancreatic Cancer. Adv Sci. 2021;8(4):2002746. doi:10.1002/advs.202002746.⁹⁶ (C) Schematic illustration of the preparation of IR775@Met@Lip and the mechanism of enhanced photodynamic immunotherapy mediated by reversing hypoxia and decreasing PD-L1 expression in vivo. Reprinted with permission from Xiong W, Qi L, Jiang N, et al. Metformin Liposome-Mediated PD-L1 Downregulation for Amplifying the Photodynamic Immunotherapy Efficacy. ACS Appl Mater Interfaces. 2021;13(7):8026–8041. doi:10.1021/acsami.0c21743. Copyright 2021 American Chemical Society.⁹⁷

Figure 6 Illustration of IMD@Hf-DBP/αCD47 plus radiotherapy and PDT. (A) The design of RT-PDT induced ICD combined with the immunoadjuvant and ICB to systemically eradicate tumors. (B) Flow cytometry analysis of mature DCs. (C) Fluorescence intensity of MHC-II. *P < 0.05, and ***P < 0.005 from control. (D) Tumor growth curves with various treatments in CT26-bearing murine model. Black and red arrows refer to intratumoral injection and X-ray irradiation, respectively.

Note: Reprinted with permission from Ni K, Luo T, Culbert A, Kaufmann M, Jiang X, Lin W. Nanoscale Metal-Organic Framework Co-delivers TLR-7 Agonists and Anti-CD47 Antibodies to Modulate Macrophages and Orchestrate Cancer Immunotherapy. J Am Chem Soc. 2020;142(29):12579–12584. doi:10.1021/jacs.0c05039. Copyright 2020 American Chemical Society.¹¹⁷

Wang M, Rao J, Wang M, et al. Cancer photo-immunotherapy: from bench to bedside. Theranostics. 2021;11(5):2218–2231. doi:10.7150/thno.53056

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Sun F, Zhu Q, Li T, et al. Regulating Glucose Metabolism with Prodrug Nanoparticles for Promoting Photoimmunotherapy of Pancreatic Cancer. Adv Sci. 2021;8(4):2002746. doi:10.1002/advs.202002746

 Web of Science ®Google Scholar

Xiong W, Qi L, Jiang N, et al. Metformin Liposome-Mediated PD-L1 Downregulation for Amplifying the Photodynamic Immunotherapy Efficacy. ACS Appl Mater Interfaces. 2021;13(7):8026–8041. doi:10.1021/acsami.0c21743

 PubMedGoogle Scholar

Ni K, Luo T, Culbert A, Kaufmann M, Jiang X, Lin W. Nanoscale Metal-Organic Framework Co-delivers TLR-7 Agonists and Anti-CD47 Antibodies to Modulate Macrophages and Orchestrate Cancer Immunotherapy. J Am Chem Soc. 2020;142(29):12579–12584. doi:10.1021/jacs.0c05039

 PubMedGoogle Scholar