A Versatile Nanoplatform for Broad-Spectrum Immunotherapy by Reversing the Tumor Microenvironment

Abstract

Immunotherapy is currently an important adjuvant therapy for malignant tumors besides surgical treatment. However, the heterogeneity and low immunogenicity of the tumor are two main challenges of the immunotherapy. Here, we have constructed a nanoplatform (CP@mRBC-PpIX) to realize reversion of the tumor acidosis and hypoxia through alkali and oxygen generation triggered by tumor acidosis. By targeting tumor universal features other than endogenous biomarkers, it was found that CP@mRBC-PpIX could polarize tumor-associated macrophages to anti-tumor M1 phenotype macrophages to enhance tumor immune response. Furthermore, under regional light irradiation, the reactive oxygen species produced by photosensitizers located in CP@mRBC-PpIX could increase the immunogenicity of tumors, so that tumor changes from an immunosuppressive “cold tumor” to an immunogenic “hot tumor,” thereby increasing the infiltration and response of T cells, further amplifying the effect of immunotherapy. This strategy circumvented the problem of tumor heterogeneity to realize a kind of broad-spectrum immunotherapy, which could effectively prevent tumor metastasis and recurrence.

Cell membrane coated nanoparticles as a biomimetic drug delivery platform for enhancing cancer immunotherapy

“…12 Commonly used photosensitizers include protoporphyrin IX (PpIX), methylene blue (MB), chlorin e6 (Ce6), and low-wavelength photosensitizers. 144,166,167 Despite its potential for highly effective and non-invasive cancer therapy, PDT's progress remains hindered by the limited availability of suitable photosensitizers and delivery challenges.…”

“…For instance, through the chimeric peptide with electrostatic interaction and hydrophobic effect, PpIX was inserted into the erythrocyte membranes tightly, forming a multifunctional nanoplatform CP@mRBC-PpIX after coating copper peroxide (CP) NPs. 144 Given the variability in materials with distinct absorption spectra and phototherapeutic properties, the selection of photosensitizers should be customized based on disease characteristics, patient conditions, and research or clinical treatment objectives.…”

Multivalence Manganese Mediated Dual ROS Generator for Augmented Chemodynamic Therapy and Activated Antitumor Immunogenic Responses

“…4,5 Moreover, the cytosolic damage caused by CDT has been demonstrated as an effective modality to trigger immunogenic cell death (ICD), 6−9 which converts the "cold tumor" into the "hot tumor" by sending an "eat me" signal to the immune system. 10 Specifically, abnormal levels of damage-associated molecular patterns (DAMPs), such as exposure of calreticulin (CRT), exocytosis of high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP), could be observed in ICD. 11−13 These phenomena stimulate the maturation of dendritic cells (DCs) for antigen presentation, enhancing the proliferation of cytotoxic T cells (CD4 + /CD8 + T cells), increasing the secretion of inflammatory cytokines (IL-2, TNF-α, IFN-γ), and initiating an immune response to effectively resist the primary tumor and inhibit the metastases.…”

“…Chemodynamic therapy (CDT), relying on the specific acidic microenvironment and high H 2 O 2 levels to generate toxic hydroxyl radicals (·OH) through a Fenton or Fenton-like reaction, − with the negligible damage to normal tissue, has been considered as an emerging and effective approach for antitumor treatment. , Moreover, the cytosolic damage caused by CDT has been demonstrated as an effective modality to trigger immunogenic cell death (ICD), − which converts the “cold tumor” into the “hot tumor” by sending an “eat me” signal to the immune system . Specifically, abnormal levels of damage-associated molecular patterns (DAMPs), such as exposure of calreticulin (CRT), exocytosis of high mobility group box 1 (HMGB1), and adenosine triphosphate (ATP), could be observed in ICD. − These phenomena stimulate the maturation of dendritic cells (DCs) for antigen presentation, enhancing the proliferation of cytotoxic T cells (CD4 + /CD8 + T cells), increasing the secretion of inflammatory cytokines (IL-2, TNF-α, IFN-γ), and initiating an immune response to effectively resist the primary tumor and inhibit the metastases. − However, the efficacy of traditional CDT and CDT triggered ICD are hampered by the single type of ROS generation and low ROS generation efficiency .…”

Aptamer-Gold Nanocage Composite for Photoactivated Immunotherapy

“…Because of the capability of spatiotemporal control, photothermal therapy (PTT) could achieve precise therapy through light targeting. − We are convinced that the combination of aptamer therapy and PTT could solve the side effects of ICB fundamentally and enhance the antitumor efficacy.…”