Nanomedicine Strategies for Heating "Cold" Ovarian Cancer (OC): Next Evolution in Immunotherapy of OC

Abstract

Immunotherapy has revolutionized cancer treatment, dramatically improving survival rates of melanoma and lung cancer patients. Nevertheless, immunotherapy is almost ineffective against ovarian cancer (OC) due to its cold tumor immune microenvironment (TIM). Many traditional medications aimed at remodeling TIM are often associated with severe systemic toxicity, require frequent dosing, and show only modest clinical efficacy. In recent years, emerging nanomedicines have demonstrated extraordinary immunotherapeutic effects for OC by reversing the TIM because the physical and biochemical features of nanomedicines can all be harnessed to obtain optimal and expected tissue distribution and cellular uptake. However, nanomedicines are far from being widely explored in the field of OC immunotherapy due to the lack of appreciation for the professional barriers of nanomedicine and pathology, limiting the horizons of biomedical researchers and materials scientists. Herein, a typical cold tumor-OC is adopted as a paradigm to introduce the classification of TIM, the TIM characteristics of OC, and the advantages of nanomedicines for immunotherapy. Subsequently, current nanomedicines are comprehensively summarized through five general strategies to substantially enhance the efficacy of immunotherapy by heating the cold OC. Finally, the challenges and perspectives of this expanding field for improved development of clinical applications are also discussed.

Keywords: immunotherapy; nanomaterials; nanomedicines; ovarian cancer; tumor immune microenvironment.

Figure 1

Current status of OC treatment. A) Changes in mortality of OC, melanoma, lung cancer, and all sites. B) Mortality of different stages of OC. C) The evolution timeline of OC systemic therapy.

Figure 2

Schematic illustration of developing nanomaterials in OC immunotherapy. A–E) Nanomaterials used in exploring new treatments for cancer vaccines: TAM repolarization inducer, antigen presentation enhancer, BiTEs, and ICD inducers. (a–e) Therapeutic effects and mechanisms of cancer vaccines: TAM repolarization inducer, antigen presentation enhancer, BiTEs, and ICD inducers in the TIM of OC.

Figure 3

The immune process and how it is hindered by the cold TIM of OC. A) Four steps of an anticancer immune response. Step 1: tumor site is infiltrated with various immunocompetent cells and factors. Step 2: macrophages engulf necrotic tumor cells and release inflammatory cytokines. Step 3: DCs capture tumor cells and present antigens to T cells. Step 4: effector T cells kill tumor cells by releasing toxic substances to tumor cells. B) Analysis of all five immune cell types and four analyzed tumor types (MEL = melanoma, LUAD = lung adenocarcinoma, LUSC = lung squamous cancer, OC = ovarian cancer). These data comprise all 965 tissue slides from 177 patients. C) OC “cold” immune microenvironment. D) Pathways of OC TIM to block anticancer immunity response. E–G) A biological barrier preventing immune cell infiltration and migration in OC. (E) OC cells disseminate throughout the peritoneal cavity and metastasize across body cavities through ascites. (F) Permeability of peritoneal capillaries and blockage of lymphatic return by cancer cells lead to ascites. Ascites recruits immunosuppressive cells, suppresses neutrophils, and prompts TAMs to release migration inhibitory factors to stop the tumor‐killing ability of natural killer (NK) cells. (G) The release of angiogenic growth factors in OC inhibits the expression of adhesion molecules, preventing T cells from adhering to and traversing the endothelium.

Figure 4

Development advantages of nanomaterials in OC immunotherapy. A) Four drug development strategies owing to the superior properties of nanomaterials. B) Three commonly used administration routes of nanomedicines in OC treatment. C) Nanomedicines achieve passive targeting through the EPR effect. They enter the tumor target through irregular intercellular spaces at the cancerous site. D) Nanomedicine surface modification with specific targeting molecules to achieve active targeting by recognizing and binding to tumor cell surface targets.

Figure 5

Strategies of nanovaccine in OC immunotherapy. A) Schematic illustration of the therapeutic mechanism of nanovaccines in OC. (a) Adjuvanted cancer vaccines are injected into OC tumor sites to induce an immune response by modulating DC recruitment, enhancing antigen presentation, and priming naive T cells. (b) Adjuvant and antigen composite cancer vaccines enter the lymph to actively deliver and present OC antigens and activate naive T cells. B) Schematic (not to real scale) of the fabrication, in vivo administration, and in vivo actuation of Qβ‐motors as an active Qβ VLP release alternative in ovarian tumors. Additional schematic (not to real scale) of the Qβ‐motors preparation. Reproduced with permission.^{[ 85 ]} Copyright 2020, Wiley‐VCH. C) Cryosilicification and adsorption of PAMPs to cancer cells. Blue motifs, CpG; purple motifs, MPL; red motifs, PEI. D) Percent and number of IP CD4+ and CD8+ T cells with naive (CD44− CD62L high), central memory (CD44+ CD62L high), and effector memory (CD44+ CD62L low) phenotypes. Reproduced with permission.^{[ 89 ]} Copyright 2019, Springer Nature.

Figure 6

Development strategies for nanomedicine‐induced TAM repolarization. A) Schematic illustration of the nanomedicines heating OC by repolarizing TAM. Drug‐ or gene‐induced repolarization of tumor‐associated macrophages reverses the immunosuppressive TIM. B) An illustration of the planned clinical application, designed to treat OC patients with repeated intraperitoneal infusions of mRNA nanoparticles. C) Heat map of signature gene expression in macrophages isolated from mice treated with IRF5‐NPs versus control PBS. D) Design of macrophage‐targeted polymeric NPs formulated with mRNAs encoding key regulators of macrophage polarization. E) PBS or IRF5/IKKβ NPs (50 µg mRNA/dose) have been injected and stained for the indicated myeloid and lymphocyte markers. Scale bar: 100 µm. Tu, tumor, Mes, mesentery. Reproduced with permission.^{[ 101 ]} Copyright 2019, Springer Nature.

Figure 7

Development strategies for nanomedicines to restore or mimic DC function to increase antigen presentation. A) Schematic illustration of nanomedicines improving OC antigen presentation. (a) Restoring DC function or (b) developing artificial DCs to enhance antigen presentation and activate T cells. B) Schematic illustration of the preparation process of blank‐nanoemulsion (Blank‐NE), α‐tocopherol‐nanoemulsion (T‐NE), KIRA6‐nanoemulsion (K‐NE), and KT‐NE. C) The proliferation of SPLCs primed by DCs or PBS‐, T‐NE‐, K‐NE‐, and KT‐NE‐treated TIDCs were evaluated by CFSE dilution. D) Cellular morphology of murine BMDCs generated in vitro. Reproduced with permission.^{[ 112 ]} Copyright 2022, Elsevier Ltd. E) Schematic illustration for the preparation of a mini DC. Reproduced under the terms of a CC‐BY license.^{[ 61 ]} Copyright 2020, The Authors. Published by Wiley‐VCH.

Figure 8

Development strategies for nanomedicines to increase T cell homing properties. A) Schematic illustration of nanomedicines increasing T cell infiltration. Bispecific T receptors recruit T cells to infiltrate tumors and promote T cell binding to cancer cells. B) Schematic diagram of MC‐MIL‐88A development strategy. C) Binding specificity of anti‐CD3/anti‐EpCAM to EpCAM‐positive SKOV3 cells at different concentrations of BiTE. Reproduced with permission.^{[ 117 ]} Copyright 2020, Elsevier Ltd. D) Binding of BsAb_EPH on CD3+ T cells. E) Binding of BsAb_EPH on EpCAM‐positive SKOV3 cells. F) A chart comparing luciferase activity in individual organs from the mice 8 h post‐transfection with MC encoding luciferase reporter gene (MC.luc). G) BsAb_EPH expression in mice after intraperitoneal injection of CaPO‐MC.BsAb_EPH complex. H) Bioluminescence images of individual mice. Reproduced with permission.^{[ 121 ]} Copyright 2020, Elsevier Ltd.

Figure 9

Development strategy of nanomedicine‐induced ICD for multitherapeutic OC immunotherapy. A) Schematic illustration of multifunctional nanomedicines heating tumors through ICD. Photodynamic/sonodynamic therapy induces immunogenic death of dying cells to trigger the immune response. B) Preparation processes of Fe₃O₄‐ICG@IRM nanoparticles. C) CLSM images of ID8‐M, RBC‐M, a mixture of ID8‐M and RBC‐M, and the fused IRM vesicles. Scale bars = 5 µm. D) CLSM images of fused IRMs incubated with ID8 cells for 3 h. Scale bars = 20 µm. E) The proportion of CD4+ and F) CD8a+ cells in the tumor‐draining lymph nodes and the spleen at 48 h after intratumoral injection of Fe₃O₄‐ICG@IRM in the left flank of ID8 bilateral tumor‐bearing mice with or without NIR radiation. G) In vivo fluorescence images showing tumor retention of Fe₃O₄‐ICG@RBC‐M, Fe₃O₄‐ICG@ID8‐M, and Fe₃O₄‐ICG@IRM over 24 h. Reproduced with permission.^{[ 127 ]} Copyright 2021, American Chemical Society.