Recent Advances in Strategies for Addressing Hypoxia in Tumor Photodynamic Therapy

Photodynamic therapy (PDT) is a treatment modality that uses light to target tumors and minimize damage to normal tissues. It offers advantages including high spatiotemporal selectivity, low side effects, and maximal preservation of tissue functions. However, the PDT efficiency is severely impeded by the hypoxic feature of tumors. Moreover, hypoxia may promote tumor metastasis and tumor resistance to multiple therapies. Therefore, addressing tumor hypoxia to improve PDT efficacy has been the focus of antitumor treatment, and research on this theme is continuously emerging. In this review, we summarize state-of-the-art advances in strategies for overcoming hypoxia in tumor PDTs, categorizing them into oxygen-independent phototherapy, oxygen-economizing PDT, and oxygen-supplementing PDT. Moreover, we highlight strategies possessing intriguing advantages such as exceedingly high PDT efficiency and high novelty, analyze the strengths and shortcomings of different methods, and envision the opportunities and challenges for future research.

Tumor Hypoxia Heterogeneity Affects Radiotherapy: Inverse-Percolation Shell-Model Monte Carlo Simulations

Tumor hypoxia was discovered a century ago, and the interference of hypoxia with all radiotherapies is well known. Here, we demonstrate the potentially extreme effects of hypoxia heterogeneity on radiotherapy and combination radiochemotherapy. We observe that there is a decrease in hypoxia from tumor periphery to tumor center, due to oxygen diffusion, resulting in a gradient of radiative cell-kill probability, mathematically expressed as a probability gradient of occupied space removal. The radiotherapy-induced break-up of the tumor/TME network is modeled by the physics model of inverse percolation in a shell-like medium, using Monte Carlo simulations. The different shells now have different probabilities of space removal, spanning from higher probability in the periphery to lower probability in the center of the tumor. Mathematical results regarding the variability of the critical percolation concentration show an increase in the critical threshold with the applied increase in the probability of space removal. Such an observation will have an important medical implication: a much larger than expected radiation dose is needed for a tumor breakup enabling successful follow-up chemotherapy. Information on the TME’s hypoxia heterogeneity, as shown here with the numerical percolation model, may enable personalized precision radiation oncology therapy.

Correlation-based and feature-driven mutation signature analyses to identify genetic features associated with DNA mutagenic processes in cancer genomes

Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.

RNA Hydrogel Combined with MnO2 Nanoparticles as a Nano-Vaccine to Treat Triple Negative Breast Cancer

Hypoxia is not only the reason of tumor metastasis but also enhances the spread of cancer cells from the original tumor site, which results in cancer recurrence. Herein, we developed a self-assembled RNA hydrogel that efficiently delivered synergistic DNA CpG and short hairpin RNA (shRNA) adjuvants, as well as MnO2 loaded-photodynamic agent chlorine e6 (MnO2@Ce6), and a chemotherapy drug doxorubicin (DOX) into MDA-MB-231cells. The RNA hydrogel consists of one tumour suppressor miRNA (miRNA-205) and one anti-metastatic miRNA (miRNA-182), both of which showed an outstanding effect in synergistically abrogating tumours. The hydrogel would be dissociated by endogenous Dicer enzyme to release loaded therapeutic molecules, and in the meantime induce decomposition of tumor endogenous H2O2 to relieve tumor hypoxia. As a result, a remarkable synergistic therapeutic effect is achieved through the combined chemo-photodynamic therapy, which simultaneously triggers a series of anti-tumor immune responses. Besides, the hydrogel as the carrier which modified aptamer to targeted MDA-MB-231 has the advantages of good biocompatibility and low cytotoxicity. This strategy could be implemented to design any other microRNA (miRNA) as the carrier, combined with other treatment methods to treat human cancer, thereby overcoming the limitations of current cancer therapies.

Neutrophil Depletion Enhanced the Clostridium novyi-NT Therapy in Mouse and Rabbit Tumor Models

Background Hypoxia is a prominent feature of solid tumors and can function as fertile environment for oncolytic anaerobic bacteria such as Clostridium novyi-NT (C. novyi-NT) where it can induce tumor destruction in mice and patients. However, two major obstacles have limited its use, namely the host inflammatory response and the incomplete clearance of normoxic tumor areas. Methods In this study, we first used a subcutaneous tumor model of a glioblastoma (GBM) cell line in immunocompetent mice to investigate the local distribution of tumor hypoxia, kinetics of C.novyi-NT germination and spread, and the local host immune response. We subsequently applied the acquired knowledge to develop a C.novyi-NT therapy in an orthotopic rabbit brain tumor model. Results We found that local accumulation of granular leukocytes, mainly neutrophils, could impede the spread of bacteria through the tumor and prevented complete oncolysis. Depletion of neutrophils via anti-Ly6G antibody or bone marrow suppression using hydroxyurea significantly improved tumor clearance. We then applied this approach to rabbits implanted with an aggressive intracranial brain tumor and achieved long term survival in majority of the animals without apparent toxicity. Conclusion These results indicated that depleting neutrophils can greatly enhance the safety and efficacy of C.novyi-NT cancer therapy for brain tumors.