Photodynamic Modulation of Endoplasmic Reticulum and Mitochondria Network Boosted Cancer Immunotherapy.

Immunogenic cell death (ICD) represents a promising approach for enhancing tumor therapy efficacy by inducing antitumor immune response. However, current ICD inducers often have insufficient endoplasmic reticulum (ER) enrichment and ineffectiveness in tumor immune escape caused by ER-mitochondria interaction. In this study, a kind of photoactivatable probe, THTTPy-PTSA, which enables sequential targeting of the ER and mitochondria is developed. THTTPy-PTSA incorporates p-Toluenesulfonamide (PTSA) for ER targeting, and upon light irradiation, the tetrahydropyridine group undergoes a photo oxidative dehydrogenation reaction, transforming into a pyridinium group that acts as a mitochondria-targeting moiety. The results demonstrate that THTTPy-PTSA exhibits exceptional subcellular translocation from the ER to mitochondria upon light irradiation treatment, subsequently triggers a stronger ER stress response through a cascade-amplification effect. Importantly, the augmented ER stress leads to substantial therapeutic efficacy in a 4T1 tumor model by eliciting the release of numerous damage-associated molecular patterns, thereby inducing evident and widespread ICD, consequently enhancing the antitumor immune efficacy. Collectively, the findings emphasize the pivotal role of photodynamic modulation of the ER-mitochondria network, facilitated by THTTPy-PTSA with precise spatial and temporal regulation, in effectively bolstering the antitumor immune response. This innovative approach presents a promising alternative for addressing the challenges associated with cancer immunotherapy.

Precise pancreatic cancer therapy through targeted degradation of mutant p53 protein by cerium oxide nanoparticles.

BACKGROUND: In a significant proportion of cancers, point mutations of TP53 gene occur within the DNA-binding domain, resulting in an abundance of mutant p53 proteins (mutp53) within cells, which possess tumor-promoting properties. A potential and straightforward strategy for addressing p53-mutated cancer involves the induction of autophagy or proteasomal degradation. Based on the previously reported findings, elevating oxidative state in the mutp53 cells represented a feasible approach for targeting mutp53. However, the nanoparticles previous reported lacked sufficient specificity of regulating ROS in tumor cells, consequently resulted in unfavorable toxicity in healthy cells. RESULTS: We here in showed that cerium oxide CeO2 nanoparticles (CeO2 NPs) exhibited an remarkable elevated level of ROS production in tumor cells, as compared to healthy cells, demonstrating that the unique property of CeO2 NPs in cancer cells provided a feasible solution to mutp53 degradation. CeO2 NPs elicited K48 ubiquitination-dependent degradation of wide-spectrum mutp53 proteins in a manner that was dependent on both the dissociation of mutp53 from the heat shock proteins Hsp90/70 and the increasing production of ROS. As expected, degradation of mutp53 by CeO2 NPs abrogated mutp53-manifested gain-of-function (GOF), leading to a reduction in cell proliferation and migration, and dramatically improved the therapeutic efficacy in a BxPC-3 mutp53 tumor model. CONCLUSIONS: Overall, CeO2 NPs increasing ROS specifically in the mutp53 cancer cells displayed a specific therapeutic efficacy in mutp53 cancer and offered an effective solution to address the challenges posed by mutp53 degradation, as demonstrated in our present study.

Crizotinib Nanomicelles Synergize with Chemotherapy through Inducing Proteasomal Degradation of Mutp53 Proteins.

TP53 missense mutations that express highly stabilized mutant p53 protein (mutp53) driving tumorigenesis have been witnessed in a considerable percentage of human cancers. The attempt to induce degradation of mutp53 has thus been an attractive strategy to realize precise antitumor therapy, but currently, there has been no FDA-approved medication for mutp53 cancer. Herein, we discovered a small molecule compound crizotinib, an FDA-approved antitumor drug, exhibited outstanding mutp53-degrading capability. Crizotinib induced ubiquitination-mediated proteasomal degradation of wide-spectrum mutp53 but not the wild-type p53 protein. Degradation of mutp53 by crizotinib eliminated mutp53-conferred gain-of-function (GOF), leading to reduced cell proliferation, migration, demise, and cell cycle arrest, as well as enhanced sensitivity to doxorubicin-elicited killing in mutp53 cancer. To alleviate the side effects and improve the therapeutic effect, we adopted poly(ethylene glycol)-polylactide-co-glycolide (PEG-PLGA) nanomicelles to deliver the hydrophobic drugs doxorubicin and crizotinib, demonstrating that crizotinib nanomicelles effectively enhanced doxorubicin-elicited anticancer efficacy in a p53Y220C pancreatic cancer in vitro and in vivo via mutp53 degradation induced by crizotinib, manifesting its promising application in clinical practice. Our work therefore revealed that crizotinib exerted significant synergistic chemotherapy with doxorubicin and suggested a novel combination therapeutic strategy for targeting p53 cancer in further clinical application.

Enhancing anti-tumor effect of ultrasensitive bimetallic RuCu nanoparticles as radiosensitizers with dual enzyme-like activities.

Radiotherapy (RT), through the generation of reactive oxygen species (ROS) and DNA damage to tumor cells caused by high-energy irradiation, has been a widely applied cancer treatment strategy in clinic. However, the therapeutic effect of traditional RT is restricted by the insufficient radiation energy deposition and the side effects on normal tissues. Recently, multifunctional nano-formulations and synergistic therapy has been developed as attractive strategies for used to enhancing the efficacy and safety of RT. Herein, we show that a bimetallic nanozyme (copper-modified ruthenium nanoparticles, RuCu NPs), containing the high atomic number (Z) element Ru as a novel radiosensitizer, offers an ideal solution to RT sensitization, with ultrasensitive peroxidase (POD)-like activity and catalase (CAT)-like activity. Density functional theory (DFT) calculations also clarified the optimal POD-like catalytic ratio of RuCu NPs and further revealed the mechanism of its supper catalytic activity. Under X-ray exposure, RuCu NPs coated with poly(ethylene glycol) (PEG) exhibited simultaneously improved the ROS production and relieved tumor hypoxia in the acid tumor microenvironment (TME), and demonstrated remarkable therapeutic efficacy in the MDA-MB-231 breast cancer model. Our results provide a proof-of-concept for a RT sensitization strategy, which combine the intrinsic nature of high-Z element and the advantages of nanozymes to overcome the tricky drawbacks existed in radiotherapy, and further open a new direction of exploring novel nanozyme-based strategies for tumor catalytic therapy and synergistic radiotherapy.