High‐Z‐Sensitized Radiotherapy Synergizes with the Intervention of the Pentose Phosphate Pathway for In Situ Tumor Vaccination

Abstract

Different from conventional vaccines, in situ vaccination could conveniently convert established tumors into a "vaccine factory" to release various tumor antigens for stimulating and diversifying antitumor T-cell response. [3] Radiation therapy (RT) is a widely used local therapy of malignancies and exhibits great potential in inducing in situ tumor vaccine effect. [4] However, even potentiated by CBI, RT could only lead to mild to moderate immune response within nonirradiated tumors, which is far less than medical needs. [5] Therefore, it is quite meaningful to boost RT-mediated in situ vaccination to extend its therapeutic effect to the whole body.To achieve this goal, a possible way could be potentiating RT-induced immunogenic cell death (ICD). ICD is a death modality accompanied by releasing tumor antigens and damage-associated molecular patterns, including calreticulin (CRT), high mobility group protein B1 (HMGB1), etc., which could provide antigens and adjuvants for tumor vaccination. [6] Currently, some studies have indicated that oxidative stress and DNA damage within tumor cells could potentially result in ICD. [7] However, due to the insufficient deposition of X-ray within tumor tissues, only low level of reactive oxygen species (ROS) could be produced to induce oxidative stress upon the recommended radiation doses. To address this problem, radiosensitizers based on high-Z elements are being developed widely to deposit X-ray for amplifying RT-induced oxidative stress. Of note, HfO 2 nanoparticles (Hensify) have been approved in Europe for locally advanced soft tissue sarcoma treatment [8] and are confirmed to augment RT-mediated antitumor immunity effect in many clinical trials. However, their slight improvements suggest the room for optimization. [9] The pentose phosphate pathway (PPP) is a branch of glycolysis and hyperactive in most tumors, [10] which could provide abundant NADPH and ribose 5-phosphate to maintain redox and nucleotides homeostasis, respectively. [11] NADPH is a central player in cellular antioxidant system, which not only mediates GSH synthesis, [12] but also acts as an electron donor to reduce oxidized GSH and thioredoxin (Trx, an important In situ tumor vaccination is preliminarily pursued to strengthen antitumor immune response. Immunogenic tumor cell death spontaneously releases abundant antigens and adjuvants for activation of dendritic cells, providing a paragon opportunity for establishing efficient in situ vaccination. Herein, Phy@PLGdH nanosheets are constructed by integrating physcion (Phy, an inhibitor of the pentose phosphate pathway (PPP)) with layered gadolinium hydroxide (PLGdH) nanosheets to boost radiation-therapy (RT)-induced immunogenic cell death (ICD) for potent in situ tumor vaccination. It is first observed that sheet-like PLGdH can present superior X-ray deposition and tumor penetrability, exhibiting improved radiosensitization in vitro and in vivo. Moreover, the destruction of cellular nicotinamide adenine dinucleotide phosphate (NADPH) and nucleotide...

Immunogenic Cell Death Activates the Tumor Immune Microenvironment to Boost the Immunotherapy Efficiency

“…[ 112 ] For this reason, ICD have been proposed as potential vaccination in situ without sophisticated procedures and ethical concerns compared with traditional vaccines. [ 113 ] Unmethylated cytosine‐phosphate‐guanine (CpG), an immunostimulatory nucleic acid, is a powerful toll‐like receptor‐9 (TLR9) agonist to induce a cascade of adaptive and innate immune responses, and it has been widely used as an adjuvant. [ 114 ] CpG can specifically bind to TLR9 to induce the production of cytokines such as IFN‐ γ , IL‐12, IL‐6, TNF‐ α , and increase the level of co‐stimulatory molecules expressed by B cells and DCs.…”

Oxygen tank for synergistic hypoxia relief to enhance mitochondria-targeted photodynamic therapy

“…Notably, oxygen supply and subcellular targeted ROS generation increase the therapeutic sensitivity to various interventions [61][62][63]. ROS-mediated immunogenic cell death may boost an antitumor immune response and amplify immunotherapy [64,65]. Oxidized mitochondrial DNA triggered by ROS activates STING signaling and promotes anti-tumor effect [66][67][68].…”

Ignored role of polyphenol in boosting reactive oxygen species generation for polyphenol/chemodynamic combination therapy

“…Reactive oxygen species (ROS) are a group of highly reactive ions or free radicals, including singlet oxygen ( 1 O 2 ), hydroxyl radicals (•OH), superoxide anions (O 2 • − ), and peroxides (O 2 2− ) [ 1 , 2 ]. In malignant tumor cells, excessive ROS can be utilized to trigger oxidative stress, leading to DNA damage [ 3 ], protein inactivation [ 4 ], phospholipid membrane peroxidation, and final cell apoptosis [ 5 ]. In this case, chemodynamic therapy (CDT), utilizing Fenton/Fenton-like reactions triggered by the tumor microenvironment (TME) for promoting ROS accumulation, has been recently developed and become a popular research focus for cancer treatment [ [6] , [7] , [8] , [9] ].…”