Photodynamic Therapy-Induced Anti-Tumor Immunity: Influence Factors and Synergistic Enhancement Strategies

Abstract

Photodynamic therapy (PDT) is an approved therapeutic procedure that exerts cytotoxic activity towards tumor cells by activating photosensitizers (PSs) with light exposure to produce reactive oxygen species (ROS). Compared to traditional treatment strategies such as surgery, chemotherapy, and radiation therapy, PDT not only kills the primary tumors, but also effectively suppresses metastatic tumors by activating the immune response. However, the anti-tumor immune effects induced by PDT are influenced by several factors, including the localization of PSs in cells, PSs concentration, fluence rate of light, oxygen concentration, and the integrity of immune function. In this review, we systematically summarize the influence factors of anti-tumor immune effects mediated by PDT. Furthermore, an update on the combination of PDT and other immunotherapy strategies are provided. Finally, the future directions and challenges of anti-tumor immunity induced by PDT are discussed.

Keywords: combination therapy; influence factors; innate immunity; photodynamic therapy; specific immunity.

Figure 1

The mechanism of action of photodynamic therapy.

Figure 2

Mechanism of photodynamic therapy-induced immune effects.

Scheme 1

Chemical structure of the PSs that can induce immune effects.

Figure 3

(A) Confocal microscopy showed co-localization of porphyrins III with ER, scale bar 20 μm. (B) Quantitative analyses of HMGB1 release. (C) Quantitative analyses of ATP release. (D) Flow cytometry analysis showed maturation of BMDCs in vitro induced by different treatment killed cancer cells. (E) Volume changes of tumors after different treatments in vivo, *, # p < 0.05 [52]. Copyright, 2021, published by the Author(s).

Figure 4

(A) Schematic of PDT immune-enhanced based on Ce6-IMDQ NPs. (B) Volume changes of tumors in primary tumors of mice after different treatments in the 4T1 tumor models. (C) Volume changes of tumors in distant tumors of mice after different treatments in the 4T1 tumor models. (D) Flow cytometric analysis of DC maturation (CD86) in tumor-draining lymph nodes after different treatments. (E) Flow cytometric analysis of the percentage of CD4⁺ and CD8⁺ T cells in spleen [58]. ** p < 0.01. Copyright, 2021, published by Royal Society of Chemistry.

Figure 5

(A) The preparation and principle of ER-targeting Ds-sP/TCPP-T^ER NPs. (B) CLSM showed co-localization of Ds-sP/TCPP-T^ER and TCPP-T^ER with the ER in 4T1 cells. (C) Western blot showed the effects of different treatments on the expression levels of HMGB1 and CRT in 4T1 cells. (D) Growth curves of primary tumors in mice after different treatments of the 4T1 tumor models. (E) Growth curves of distal tumors in mice after different treatments of the 4T1 tumor models. (F) Flow cytometry showed the proportion of IFN-γ⁺ CD8⁺ T cells in mice tumor tissues [50]. ** p < 0.01. Copyright, 2020, published by American Chemical Society.

Figure 6

(A) Schematic of oxygen-enhanced PDT-induced ICD based on ER targeting NPs. (B) CT26 cell viability after different treatments under hypoxic conditions. (C) Flow cytometry showed the percentage of CD8⁺ T cells and CD4⁺ T cells in mice spleens [49]. Copyright, 2019, published by the Author(s).

Figure 7

(A) Schematic of the preparation and function of AuNC@MnO₂ as an ICD inducer for oxygen-boosted PDT. (B) Growth curves of primary tumors in mice after different treatments of the 4T1 tumor models. (C) Growth curves of distal tumors in mice after different treatments of the 4T1 tumor models. (D) Counts of the number of metastatic lesions from resected lungs (white spots as a sign of metastatic lung nodules) [68]. * p < 0.05, ** p < 0.01, *** p < 0.001, # p < 0.05. Copyright, 2018, published by Elsevier.

Figure 8

(A) Schematic of the anti-tumor effect of ZnP@pyro. (B) Growth curves of tumors after different treatments in the 4T1 tumor models. (C) The numbers of tumor nodules in the lungs of mice. (D) Flow cytometry showed the percentage of CD8⁺ T cells and CD4⁺ T cells in mice metastases after different treatments, * p < 0.05, ** p < 0.01, *** p < 0.001 [61]. Copyright, 2016, published by American Chemical Society.

Figure 9

(A) Schematic of the preparation, function, and anti-tumor effect of LT-NTs. (B) Growth curves of tumors after different treatments in the CT26 tumor models (arrows: metastatic tumor nodules). (C) Image of lung metastasis at day 20 after tumor inoculation, *** p < 0.001 [53]. Copyright, 2021, published by American Chemical Society.