Synergistic Reinforcing of Immunogenic Cell Death and Transforming Tumor‐Associated Macrophages Via a Multifunctional Cascade Bioreactor for Optimizing Cancer Immunotherapy

Abstract

properties with low immunogenicity and the infiltration of T cells. [3] Therefore, strategies by which "cold" tumors can be transformed into "hot" tumors have been extensively researched so that more patients may obtain the benefits of ICBs therapy. The immunogenic cell death (ICD) of tumors has been proved to be an effective tool to improve the immunogenicity of tumor cells. [4] ICD occurs when specific inducers harness the host immune system to recognize and kill cancer cells by causing endoplasmic reticulum (ER) stress. [5] The dying tumor cells release damage-associated molecular patterns (DAMPs), which primarily consist of calreticulin (CRT), high mobility group box 1 (HMGB1), adenosine triphosphate (ATP), and heat shock protein 70 (HSP70). [6] Previous literature revealed that the antigen presentation efficiency of dendritic cells (DCs) was positively correlated with the DAMP content in tumors; [7] therefore, the sufficient release of DAMPs from tumor cells undergoing ICD is crucial to improve immunotherapy efficiency. Apart from the low immunogenicity of tumor cells, the counteracted innate immune system is also responsible for the poor therapeutic effect of ICBs. The suppressive immune cells in tumors, including tumor-associated macrophages (TAMs) and regulatory T cells (Tregs), always lead to immunotherapy failure because they limit T cell infiltration Immunogenic cell death (ICD) has aroused widespread attention because it can reconstruct a tumor microenvironment and activate antitumor immunity. This study proposes a two-way enhancement of ICD based on aCaO 2 @CuS-MnO 2 @HA (CCMH) nanocomposite to overcome the insufficient damageassociated molecular patterns (DAMPs) of conventional ICD-inducers. The near-infrared (NIR) irradiation (1064 nm) of CuS nanoparticles generates 1 O 2 through photodynamic therapy (PDT) to trigger ICD, and it also damages the Ca 2+ buffer function of mitochondria. Additionally, CaO 2 nanoparticles react with H 2 O to produce a large amount of O 2 and Ca 2+ , which respectively lead to enhanced PDT and Ca 2+ overload during mitochondrial damage, thereby triggering a robust ICD activation. Moreover, oxidative-damaged mitochondrial DNA, induced by PDT and released from tumor cells, reprograms the immunosuppressive tumor microenvironment by transforming tumor-associated macrophages to the M1 subphenotype. This study shows that CCMH with NIR-II irradiation can elicit adequate DAMPs and an active tumorimmune microenvironment for both 4T1 and CT26 tumor models. Combining this method with an immune checkpoint blockade can realize an improved immunotherapy efficacy and long-term protection effect for body.

Recent Developments in Nanoparticle‐Based Photo‐Immunotherapy for Cancer Treatment

“…[ 186 ] Inspired by this finding, a nanoplatform for enhanced PDT was constructed by loading ultrasmall CuS‐MnO 2 nanoparticles onto CaO 2 nanoparticles, followed by coating with hyaluronic acid for tumor cell targeting (Figure 7B). [ 187 ] After cellular uptake, the CuS component mediated NIR‐triggered PTT and PDT, which was aided by the increased oxygen generated from CaO 2 and reduced glutathione facilitated by MnO 2 . In vitro results with 4T1 cells confirmed mitochondrial injury and increased expression of CRT, HMGB1, ATP, and HSP70, which promoted the M2 to M1 transformation of macrophages.…”

“…CaO 2 nanoparticles loaded with ultrasmall CuS-MnO 2 nanoparticles and coated with hyaluronic acid. [187] Mesoporous silica nanoparticles loaded with IR780 and metformin and sealed with CeO 2 nanoparticles. [192] Immune checkpoint blockade Polydimethylsiloxane microneedles loaded with dextran nanoparticles coencapsulated with anti-CTLA4 and the photosensitizer zinc phthalocyanine.…”

“…Copyright 2021, Elsevier Ltd. B) Hyaluronic acid-camouflaged CaO 2 nanoparticles functionalized with ultrasmall CuS-MnO 2 nanoparticles can facilitate the repolarization of M2 macrophages to M1 macrophages by promoting the release of oxidatively damaged mitochondrial DNA (ox-mtDNA). Adapted with permission [187]. Copyright 2022, Wiley-VCH.…”

NIR-II Light-Activated Gold Nanorods for Synergistic Thermodynamic and Photothermal Therapy of Tumor

“…To alleviate hypoxia at the tumor site, the usual strategies are delivery of exogenous oxygen to the tumor site, − in situ generation of oxygen, − and inhibition of tumor cell oxygen consumption. − Recently, a new type of TDT has been explored by producing highly toxic alkyl radicals via thermally triggered AIPH (a thermal sensitive azo compound: 2,2′-azobis­[2-(2-imidazolin-2-yl)­propane]-dihydrochloride) decomposition. − However, the previously explored photothermal effects of nanocarriers were mainly activated by NIR-I light (650–1000 nm), such as gold nanocages, bovine serum albumin nanoparticles, Fe 5 C 2 nanoparticles, and Bi 2 Se 3 @PDA nanoparticles . The NIR-II light (1000–1700 nm) presents larger maximum permissible exposure and more efficient tissue penetration, compared with the NIR-I light. − There is a necessity to explore NIR-II light-activated TDT. , …”

Cell-surface photochemistry mediated calcium overload for synergistic tumor therapy

“…Disturbance of intracellular Ca 2+ homeostasis, especially aberrant cytosolic accumulation of free Ca 2+ (intracellular Ca2 + overload), is widely found to cause different types of cellular damage and even death. 3,4 Notably, tumor cells, which feature a higher frequency of Ca 2+ signaling, are more sensitive to Ca 2+ regulation than normal cells. 5,6 This feature might provide a new avenue for tumor treatment.…”