Recent advances in nanomedicines for photodynamic therapy (PDT)-driven cancer immunotherapy

Abstract

Cancer immunotherapy has made tremendous clinical progress in advanced-stage malignancies. However, patients with various tumors exhibit a low response rate to immunotherapy because of a powerful immunosuppressive tumor microenvironment (TME) and insufficient immunogenicity of tumors. Photodynamic therapy (PDT) can not only directly kill tumor cells, but also elicit immunogenic cell death (ICD), providing antitumor immunity. Unfortunately, limitations from the inherent nature and complex TME significantly reduce the efficiency of PDT. Recently, smart nanomedicine-based strategies could subtly modulate the pharmacokinetics of therapeutic compounds and the TME to optimize both PDT and immunotherapy, resulting in an improved antitumor effect. Here, the emerging nanomedicines for PDT-driven cancer immunotherapy are reviewed, including hypoxia-reversed nanomedicines, nanosized metal-organic frameworks, and subcellular targeted nanoparticles (NPs). Moreover, we highlight the synergistic nanotherapeutics used to amplify immune responses combined with immunotherapy against tumors. Lastly, the challenges and future expectations in the field of PDT-driven cancer immunotherapy are discussed.

Keywords: cancer immunotherapy; emerging nanomedicines; immune response; photodynamic therapy; synergistic nanotherapeutics.

Figure 1

Schematic illustration of emerging nanomedicines for PDT-driven cancer immunotherapy. The outer shell shows recent nanomedicines developed for PDT-driven cancer immunotherapy, including tumor hypoxia-reversed nanomedicines, UCNs, nanosized nMOFs, TME-responsive NPs, subcellular targeted NPs, carrier-free and small-molecule prodrug-based self-assembled NPs, and multifactor-driven nanomedicines. The inner core explains how to amplify the combination of PDT and immunotherapy, thereby improving the effect of cancer treatment.

Figure 2

Schematic illustration of various tumor hypoxia-reversed nanomedicines for PDT-driven cancer immunotherapy. (A) AuNC@MnO₂ (AM) NPs, (B) Oxygen-producing phototherapy hydrogel (POP-Gel), (C) Ce6@(Oxygen-carrying hybrid protein) NPs, (D) Oxygen-carrying fluorinated polymer NPs (FPNs). Reproduced with permission , , , . Copyright 2018, Elsevier Ltd; Copyright 2019, Elsevier Ltd; Copyright 2018, American Chemical Society; Copyright 2019, Elsevier Ltd.

Figure 3

Upconversion NPs for PDT-driven cancer immunotherapy. (A) Schematic illustration of UCN-Ce6-R837 nanoplatform-induced strong immune response, which combined with CTLA4 blockade to inhibit the relapse and metastasis of tumors. (B) DC maturation induced by various formulations. (C) Frequency of CD8⁺ CTLs\Treg cells in distant tumors treated with different formulations. (D) Growth curves of CT26 tumor-bearing mice after receiving different formulations. Reproduced with permission . Copyright 2017, American Chemical Society.

Figure 4

nMOFs for PDT-driven Cancer Immunotherapy. Mechanism of the nMOFs to induce a PDT-mediated immune response, and combination with (A) IDO inhibitor or (B) αPD-1 in cancer immunotherapy. (C) CLSM imaging of tumor cells incubated with DCFH-DA and TBP-nMOFs in (b) under dark, (c) 5% O₂ or (d) 21% O₂ under light irradiation. (D) Growth curves of 4T1 tumor-bearing mice after receiving different formulations. (E) Frequency of CD8⁺ cells in tumors treated with different formulations. Reproduced with permission , . Copyright 2016 and 2018, American Chemical Society.

Figure 5

TME-responsive NPs for PDT-driven cancer immunotherapy. (A) Schematic illustration of pH-responsive NPs for high efficient PDT, induction of ICD, and inhibition of IDO pathway. Reproduced with permission . Copyright 2020, American Chemical Society. (B) Schematic illustration of GSH-responsive NPs for PDT-induced immune response and improved tumor-targeting cancer immunotherapy. Reproduced with permission . Copyright 2019, American Chemical Society. (C) Schematic illustration of ROS-responsive NPs for cascaded amplification of PDT and strong systemic antitumor immune responses. Reproduced with permission . Copyright 2020, Elsevier Ltd. (D) Schematic illustration of Hypoxia-responsive NPs for hypoxia-triggered conversion, PDT-induced immune response and vaccine immunotherapy. Reproduced with permission . Copyright 2019, American Chemical Society.

Figure 6

Schematic illustration of various subcellular targeted NPs for improved PDT-driven cancer immunotherapy. (A) ER-targeting Ds-sP/TCPP-T^ER NPs, (B) Ce6-loaded mitochondrial-targeting NPs, (C) enzyme-driven PM-targeting PCPK NPs. Reproduced with permission , , . Copyright 2020, American Chemical Society; Copyright 2018, American Chemical Society; Copyright 2019, American Chemical Society.

Figure 7

(A) Schematic illustration of preparation of the PEG-coated co-assembled NPs of ICG and αPD-L1, in vivo local activation of cancer immunotherapy. Reproduced with permission . Copyright 2019, AAAS. (B) Schematic illustration of preparation of small molecule prodrug self-assembled NPs for in situ PDT, increased immunogenic response, cascade release of IDO inhibitor, inhibition of lung metastasis. Reproduced with permission . Copyright 2018, American Chemical Society.

Figure 8

(A) Schematic illustration of preparation of CCNV/DOX/HPPH as in Situ DC Vaccine for synergistically inducing ICD by chemotherapy and PDT, CTL activation and vaccine immunotherapy. (B) Flow cytometry characterization of CRT exposure by measuring various formulations stained with specific fluorescent probe of CRT. (C) Frequency of CD3+CD8+ TILs in tumors treated with different formulations. Reproduced with permission . Copyright 2019, American Chemical Society.

Figure 9

Schematic illustration of UCN@MOF nanostructures loaded with TPZ for cancer treatment by integration of hypoxia-activated chemotherapy, NIR light-triggered PDT and immunotherapy. Reproduced with permission . Copyright 2020, American Chemical Society.

Figure 10

(A) Schematic illustration of preparation of ER-targeting and ER-targeting FIAuNPs and FHlipos for combinational therapeutic strategies including ER-targeting PTT, ER-targeting PDT, and synergistically inducing ICD by PTT and PDT. (B) CLSM imaging of tumor sections treated with various formulation for detecting immunofluorescent staining of CD8⁺ T cells and CRT expression. Reproduced with permission . Copyright 2019, Nature publisher. (C) Schematic illustration of improved PTT/PDT-driven cancer immunotherapy by combination with both HSP60 and NRF2 to inhibit immune-resistance caused by PTT and PDT. Reproduced with permission . Copyright 2020, Elsevier Ltd.